78 results on '"Jiménez-Altayó F"'
Search Results
2. Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages
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Puig N., Montolio L., Camps-Renom P., Navarra L., Jiménez-Altayó F., Jiménez-Xarrié E., Sánchez-Quesada J.L., and Benitez S.
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immunology ,Inflammation ,Lipoproteins, LDL ,Macrophages ,Humans ,oxidized low density lipoprotein ,human ,macrophage ,triacylglycerol ,low density lipoprotein ,Triglycerides - Abstract
Electronegative low-density lipoprotein (LDL) (LDL(-)), a modified LDL that is present in blood and exerts atherogenic effects on endothelial cells and monocytes. This study aimed to determine the action of LDL(-) on monocytes differentiated into macrophages. LDL(-) and in vitro-modified LDLs (oxidized, aggregated, and acetylated) were added to macrophages derived from THP1 monocytes over-expressing CD14 (THP1-CD14). Then, cytokine release, cell differentiation, lipid accumulation, and gene expression were measured by ELISA, flow cytometry, thin-layer chromatography, and real-time PCR, respectively. LDL(-) induced more cytokine release in THP1-CD14 macrophages than other modified LDLs. LDL(-) also promoted morphological changes ascribed to differentiated macrophages. The addition of high-density lipoprotein (HDL) and anti-TLR4 counteracted these effects. LDL(-) was highly internalized by macrophages, and it was the major inductor of intracellular lipid accumulation in triglyceride-enriched lipid droplets. In contrast to inflammation, the addition of anti-TLR4 had no effect on lipid accumulation, thus suggesting an uptake pathway alternative to TLR4. In this regard, LDL(-) upregulated the expression of the scavenger receptors CD36 and LOX-1, as well as several genes involved in triglyceride (TG) accumulation. The importance and novelty of the current study is that LDL(-), a physiologically modified LDL, exerted atherogenic effects in macrophages by promoting differentiation, inflammation, and triglyceride-enriched lipid droplets formation in THP1-CD14 macrophages, probably through different receptors.
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- 2020
3. Small resistance artery disease and ACE2 in hypertension : A new paradigm in the context of COVID-19
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Galán, María, Jiménez-Altayó, F., Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia, Galán, María, Jiménez-Altayó, F., and Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia
- Abstract
This work was supported by grants from the Spanish Ministerio de Econom?a y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) (PI17/01837 to MG and SAF2014-56111-R to FJ-A); Generalitat de Catalunya (SGR-645 to FJ-A); and by CIBER on Cardiovascular Diseases (CIBERCV) (CB16/11/00257 to MG), an initiative from Carlos III National Institute of Health, Spain with co-funding from the European Regional Development Fund (ERDF). MG was supported by funds provided by ISCIII (CP15/00126, Miguel Servet I program)., This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) (PI17/01837 to MG and SAF2014-56111-R to FJ-A); Generalitat de Catalunya (SGR-645 to FJ-A); and by CIBER on Cardiovascular Diseases (CIBERCV) (CB16/11/00257 to MG), an initiative from Carlos III National Institute of Health, Spain with co-funding from, Cardiovascular disease causes almost one third of deaths worldwide, and more than half are related to primary arterial hypertension (PAH). The occurrence of several deleterious events, such as hyperactivation of the renin-angiotensin system (RAS), and oxidative and inflammatory stress, contributes to the development of small vessel disease in PAH. Small resistance arteries are found at various points through the arterial tree, act as the major site of vascular resistance, and actively regulate local tissue perfusion. Experimental and clinical studies demonstrate that alterations in small resistance artery properties are important features of PAH pathophysiology. Diseased small vessels in PAH show decreased lumens, thicker walls, endothelial dysfunction, and oxidative stress and inflammation. These events may lead to altered blood flow supply to tissues and organs, and can increase the risk of thrombosis. Notably, PAH is prevalent among patients diagnosed with COVID-19, in whom evidence of small vessel disease leading to cardiovascular pathology is reported. The SARS-Cov2 virus, responsible for COVID-19, achieves cell entry through an S (spike) high-affinity protein binding to the catalytic domain of the angiotensin-converting enzyme 2 (ACE2), a negative regulator of the RAS pathway. Therefore, it is crucial to examine the relationship between small resistance artery disease, ACE2, and PAH, to understand COVID-19 morbidity and mortality. The scope of the present review is to briefly summarize available knowledge on the role of small resistance artery disease and ACE2 in PAH, and critically discuss their clinical relevance in the context of cardiovascular pathology associated to COVID-19.
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- 2020
4. Different β-adrenoceptor subtypes coupling to cAMP or NO/cGMP pathways: implications in the relaxant response of rat conductance and resistance vessels
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Flacco, N, Segura, V, Perez-Aso, M, Estrada, S, Seller, J F, Jiménez-Altayó, F, Noguera, M A, DʼOcon, P, Vila, E, and Ivorra, M D
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- 2013
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5. Vascular hyperpolarization to β-adrenoceptor agonists evokes spreading dilatation in rat isolated mesenteric arteries
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Garland, C J, Yarova, P L, Jiménez-Altayó, F, and Dora, K A
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- 2011
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6. 439 - Sex-dependent increase of cerebral blood flow in cortex and hippocampus as a compensatory mechanism in end-of-life dementia: A MRI-ASL translational approach in models of normal and pathological aging
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Muntsant-Soria, A, primary, Jiménez-Altayó, F, additional, Jiménez-Xarrié, E, additional, and Giménez-Llort, L, additional
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- 2020
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7. Electronegative LDL (LDL(-)) induces cell differentiation and inflammatory response in THP1-CD14 macrophages
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Puig, N., Jiménez-Xarrié, E., Camps-Renom, P., Jiménez-Altayó, F., Sanchez-Quesada, J.L., and Benitez, S.
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- 2020
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8. Peroxynitrite formed during a transient episode of brain ischaemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor-stimulated rat cerebral arteries
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Onetti, Y., primary, Dantas, A. P., additional, Pérez, B., additional, McNeish, A. J., additional, Vila, E., additional, and Jiménez-Altayó, F., additional
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- 2016
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9. Different b-adrenoceptor subtypes coupling to cAMP or NO/cGMP pathways : implications in the relaxant response of rat conductance and resistance vessels
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Flacco, N, Segura, V, Perez-Aso, M, Estrada, S, Seller, JF, Jiménez-Altayó, F, Noguera, MA, D'Ocon, P, Vila, E, and Ivorra, MD
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Male ,Myocytes, Smooth Muscle ,Isoproterenol ,Nitric Oxide ,Real-Time Polymerase Chain Reaction ,b-adrenoceptor subtypes ,Research Papers ,Mesenteric Arteries ,Rats ,Vasodilation ,cGMP ,Receptors, Adrenergic, beta-3 ,cAMP ,ARN Mensajero ,Cyclic AMP ,Animals ,Endothelium, Vascular ,Receptors, Adrenergic, beta-2 ,RNA, Messenger ,Rats, Wistar ,Receptors, Adrenergic, beta-1 ,Cyclic GMP ,Aorta ,Signal Transduction - Abstract
To analyse the relative contribution of b1-, b2- and b3-adrenoceptors (Adrb) to vasodilatation in conductance and resistance vessels, assessing the role of cAMP and/or NO/cGMP signalling pathways. Experimental Approach Rat mesenteric resistance artery (MRA) and aorta were used to analyse the Adrb expression by real-time-PCR and immunohistochemistry, and for the pharmacological characterization of Adrb-mediated activity by wire myography and tissue nucleotide accumulation. Key Results The mRNAs and protein for all Adrb were identified in endothelium and/or smooth muscle cells (SMCs) in both vessels. In MRA, Adrb1 signalled through cAMP, Adrb3 through both cAMP and cGMP, but Adrb2, did not activate nucleotide formation; isoprenaline relaxation was inhibited by propranolol (β1, β2), CGP20712A (β1), and SQ22536 (adenylyl cyclase inhibitor), but not by ICI118,551 (β2), SR59230A (β3), ODQ (soluble guanylyl cyclase inhibitor), L-NAME or endothelium removal. In aorta, Adrb1 signalled through cAMP, while β2- and β3-subtypes through cGMP; isoprenaline relaxation was inhibited by propranolol, ICI118,551, ODQ, L-NAME, and to a lesser extent, by endothelium removal. CL316243 (β3-agonist) relaxed aorta, but not MRA. Conclusion and Implication Despite all three Adrb subtypes being found in both vessels, Adrb1, located in SMCs and acting through the adenylyl cyclase/cAMP pathway, are primarily responsible for vasodilatation in MRA. However, Adrb-mediated vasodilatation in aorta is driven by endothelial Adrb2 and Adrb3, but also by the Adrb2 present in SMCs, and is coupled to the NO/cGMP pathway. These results could help to understand the different physiological roles played by Adrb signalling in regulating conductance and resistance vessels. COL0135121
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- 2013
10. Peroxynitrite formed during a transient episode of brain ischaemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor-stimulated rat cerebral arteries.
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Onetti, Y., Dantas, A. P., Pérez, B., McNeish, A. J., Vila, E., and Jiménez‐Altayó, F.
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PEROXYNITRITE ,CEREBRAL ischemia ,HYPERPOLARIZATION (Cytology) ,THROMBOXANE receptors ,PROSTAGLANDIN receptors - Abstract
Aim Increased thromboxane A
2 and peroxynitrite are hallmarks of cerebral ischaemia/reperfusion (I/R). Stimulation of thromboxane/prostaglandin receptors ( TP) attenuates endothelium-derived hyperpolarization ( EDH). We investigated whether EDH-type middle cerebral artery ( MCA) relaxations following TP stimulation are altered after I/R and the influence of peroxynitrite. Methods Vascular function was determined by wire myography after TP stimulation with the thromboxane A2 mimetic 9,11-dideoxy-9α, 11α -methano-epoxy prostaglandin F2α (U46619) in MCA of Sprague Dawley rats subjected to MCA occlusion (90 min)/reperfusion (24 h) or sham operation, and in non-operated (control) rats. Some rats were treated with saline or the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron ( III) (20 mg kg−1 ). Protein expression was evaluated in MCA and in human microvascular endothelial cells submitted to hypoxia (overnight)/reoxygenation (24 h) (H/R) using immunofluorescence and immunoblotting. Results In U46619-pre-constricted MCA, EDH-type relaxation by the proteinase-activated receptor 2 agonist serine-leucine-isoleucine-glycine-arginine-leucine- NH2 ( SLIGRL) was greater in I/R than sham rats due to an increased contribution of small-conductance calcium-activated potassium channels ( SKC a ), which was confirmed by the enlarged relaxation to the SKC a activator N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine. I/R and H/R induced endothelial protein tyrosine nitration and filamentous-actin disruption. In control MCA, either cytochalasin D or peroxynitrite disrupted endothelial filamentous-actin and augmented EDH-type relaxation. Furthermore, peroxynitrite decomposition during I/R prevented the increase in EDH-type responses. Conclusion Following TP stimulation in MCA, EDH-type relaxation to SLIGRL is greater after I/R due to endothelial filamentous-actin disruption by peroxynitrite, which prevents TP-induced block of SKC a input to EDH. These results reveal a novel mechanism whereby peroxynitrite could promote post-ischaemic brain injury. [ABSTRACT FROM AUTHOR]- Published
- 2017
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11. Different β-adrenoceptor subtypes coupling to cAMP or NO/ cGMP pathways: implications in the relaxant response of rat conductance and resistance vessels.
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Flacco, N, Segura, V, Perez‐Aso, M, Estrada, S, Seller, JF, Jiménez‐Altayó, F, Noguera, MA, D'Ocon, P, Vila, E, and Ivorra, MD
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ADRENERGIC receptors ,CYCLIC adenylic acid ,CYCLIC guanylic acid ,LABORATORY rats ,VASODILATION ,CELLULAR signal transduction ,MESENTERIC artery - Abstract
Background and Purpose To analyse the relative contribution of β
1 -, β2 - and β3 -adrenoceptors ( Adrb) to vasodilatation in conductance and resistance vessels, assessing the role of cAMP and/or NO/ cGMP signalling pathways. Experimental Approach Rat mesenteric resistance artery ( MRA) and aorta were used to analyse the Adrb expression by real-time -PCR and immunohistochemistry, and for the pharmacological characterization of Adrb-mediated activity by wire myography and tissue nucleotide accumulation. Key Results The mRNAs and protein for all Adrb were identified in endothelium and/or smooth muscle cells ( SMCs) in both vessels. In MRA, Adrb1 signalled through cAMP, Adrb3 through both cAMP and cGMP, but Adrb2, did not activate nucleotide formation; isoprenaline relaxation was inhibited by propranolol (β1 , β2 ), CGP20712A (β1 ), and SQ22536 (adenylyl cyclase inhibitor), but not by ICI118,551 (β2 ), SR59230A (β3 ), ODQ (soluble guanylyl cyclase inhibitor), L- NAME or endothelium removal. In aorta, Adrb1 signalled through cAMP, while β2 - and β3 -subtypes through cGMP; isoprenaline relaxation was inhibited by propranolol, ICI118,551, ODQ, L- NAME, and to a lesser extent, by endothelium removal. CL316243 (β3 -agonist) relaxed aorta, but not MRA. Conclusion and Implication Despite all three Adrb subtypes being found in both vessels, Adrb1, located in SMCs and acting through the adenylyl cyclase/ cAMP pathway, are primarily responsible for vasodilatation in MRA. However, Adrb-mediated vasodilatation in aorta is driven by endothelial Adrb2 and Adrb3, but also by the Adrb2 present in SMCs, and is coupled to the NO/ cGMP pathway. These results could help to understand the different physiological roles played by Adrb signalling in regulating conductance and resistance vessels. [ABSTRACT FROM AUTHOR]- Published
- 2013
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12. Senescence-induced remodelling in large and small arteries of mice: impact of high-fat diet.
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Jiménez-Altayó, F., Dantas, A. P., Onetti, Y., Oliveira, M. A., Carvalho, M. H., and Vila, E.
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AGING , *WEIGHT gain , *CARDIOVASCULAR diseases risk factors - Abstract
Aging and weight gain are independent cardiovascular risk factors, which have shown to be increasingly associated. We hypothesize that high-fat intake could lead to arterial remodelling similar to that promoted by vascular aging and worsen the remodelling exerted by senescence. For this purpose we analysed structure of large (aorta) and small (mesenteric artery, MA) arteries from senescence accelerated mice (SAM) following a Western-type diet (WD; 21 % fat). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a WD for 8 weeks. At 7 months of age, aortas and MAs were dissected. In aorta, vascular structure and mature or newly synthesized collagen was analysed by morphometric analysis of haematoxylin and eosin-stained cross sections and picrosirius red, respectively. In MA, vascular structure, collagen I/III protein and mRNA expression, and nuclei distribution was evaluated by pressure myography, immunofluores-cence, RT-qPCR and confocal microscopy, respectively. Values are means ± S.E.M. compared by two way ANOVA with Bonferroni's post-test. On normal chow, weight gain, abdominal fat and cholesterol levels were comparable between strains and similarly increased after WD (Jiménez-Altayó etal., 2012). In aorta, wall thickness (WT), but not cross sectional area (CSA), was increased by senescence (SAMR1: 171.3±4.8 μm, n=7; SAMP8: 194.6±6.1 μm, n=8, p<0.05). WD only modified aortic structure in SAMR1 (control: 171.3±4.8 μm, n=7; WD: 209.8±10.0 μm, n=7, p<0.01) paralleled by an increase in mature (n=11) and newly synthesized (n=9) collagen. In MAs, senescence did not alter the wall/lumen ratio but diminished (p<0.05) the CSA and WT in association with reduced number of adventitial (SAMR1: 2339±194, n=6; SAMP8:1145±81, n=3, p<0.01) and smooth muscle (SAMR1: 3535±213, n=6; SAMP8l:2613±68, n=3, p<0.05) cells per mm³. WD decreased MA CSA (p<0.01), WT (p<0.001) and wall/lumen ratio (p<0.05) in SAMR1 paralleled by diminished adventitial (control: 2339±194, n=6; WD: 1393±269, n=6, p<0.05) and smooth muscle (control: 3535±213, n=6; WD: 2314±230, n=6, p<0.01) cells per mm³. Nevertheless, WD intake in SAMP8 did notfurther modify MA structure. Collagen I/III protein (n=4-6) and mRNA expression (n=4-6) was unaltered by senescence or diet. Therefore, senescence induces qualitatively different remodelling in large and small arteries of mice. High-fat intake promotes remodelling in non-senescent mice consistent with accelerated senescence, whereas the vasculature of senescent mice does not display any further alteration. In both cases, arterial remodelling may exacerbate vascular injury. [ABSTRACT FROM AUTHOR]
- Published
- 2013
13. Pharmacological characterization of alpha adrenoceptor-mediated motor responses in the rat colon.
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Traserra S, Grao M, Trujillo S, Jiménez-Altayó F, Vergara P, and Jimenez M
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Background: Inhibitory neuromuscular transmission in the gastrointestinal tract is mediated by intrinsic nitrergic and purinergic neurons. Purines activate G protein-coupled receptor P2Y
1 receptors, increasing intracellular Ca2+ that activates small conductance calcium-activated potassium (SKCa ) channels. Little is known about the effect of adrenergic receptor activation on intestinal smooth muscle. In vascular tissue, stimulation of α-adrenoceptors causes smooth muscle contraction, while their effect on intestinal tissue is poorly understood. This study aimed to pharmacologically characterize the effect of α-adrenoceptor activation in the rat colon, which shares similar inhibitory pathways to the human colon., Methods: Muscle bath experiments were performed with the rat proximal, mid, and distal colon oriented both circularly and longitudinally., Results: The α1 -adrenoceptor agonist phenylephrine (PE) (10-8 -10-5 M) evoked concentration-dependent relaxations of the intestinal smooth muscle from all regions and orientations. However, in the mid-circular colon at low PE concentrations, a contraction sensitive to 10-5 M phentolamine (non-selective α-adrenoceptor blocker), the neural blocker tetrodotoxin (TTX; 10-6 M), and atropine (10-6 M) was recorded. PE-induced relaxations were insensitive to TTX (10-6 M) and the nonselective β-adrenoceptor blocker propranolol (10-6 M). In contrast, PE-induced relaxations were blocked by phentolamine (10-5 M), prazosin (10-6 M) (α1 -adrenoceptor blocker), and RS17053 (10-6 M) (α1A -blocker), but not by yohimbine (10-6 M) (α2 -adrenoceptor blocker). Apamin (10-6 M), a SKCa channel blocker, abolished PE-induced relaxations., Conclusions: Contractile responses in the circular muscle of the mid colon could be attributed to α-adrenoceptors located on enteric cholinergic neurons. Stimulation of α1A -adrenoreceptors activates SKCa channels to cause smooth muscle relaxation, which constitutes a signaling pathway that shares similarities with P2Y1 receptors., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)- Published
- 2024
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14. Histone deacetylase inhibition by suberoylanilide hydroxamic acid during reperfusion promotes multifaceted brain and vascular protection in spontaneously hypertensive rats with transient ischaemic stroke.
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Díaz-Pérez A, Pérez B, Manich G, García-Aranda J, Navarro X, Penas C, and Jiménez-Altayó F
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- Male, Rats, Animals, Mice, Vorinostat pharmacology, Vorinostat therapeutic use, Histone Deacetylases, Rats, Inbred SHR, Histones, Brain, Infarction, Edema, Brain Ischemia drug therapy, Stroke drug therapy, Ischemic Stroke
- Abstract
Hypertension is the most prevalent modifiable risk factor for stroke and is associated with worse functional outcomes. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid (SAHA) modulates gene expression and has emerged as a promising therapeutic approach to reduce ischaemic brain injury. Here, we have tested the therapeutic potential of SAHA administered during reperfusion in adult male spontaneously hypertensive (SHR) rats subjected to transient middle cerebral artery occlusion (tMCAO; 90 min occlusion/24 h reperfusion). Animals received a single dose of SAHA (50 mg/kg) or vehicle i.p. at 1, 4, or 6 h after reperfusion onset. The time-course of brain histone H3 acetylation was studied. After tMCAO, drug brain penetrance and beneficial effects on behavioural outcomes, infarct volume, oedema, angiogenesis, blood-brain barrier integrity, cerebral artery oxidative stress and remodelling, and brain and vascular inflammation were evaluated. SAHA increased brain histone H3 acetylation from 1 to 6 h after injection, reaching the ischaemic brain administered during reperfusion. Treatment given at 4 h after reperfusion onset improved neurological score, reduced infarct volume and oedema, attenuated microglial activation, prevented exacerbated MCA angiogenic sprouting and blood-brain barrier breakdown, normalised MCA oxidative stress and remodelling, and modulated brain and cerebrovascular cytokine expression. Overall, we demonstrate that SAHA administered during early reperfusion exerts robust brain and vascular protection after tMCAO in hypertensive rats. These findings are aligned with previous research in ischaemic normotensive mice and help pave the way to optimise the design of clinical trials assessing the effectiveness and safety of SAHA in ischaemic stroke., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be interpreted as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2024
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15. Serum from Stroke Patients with High-Grade Carotid Stenosis Promotes Cyclooxygenase-Dependent Endothelial Dysfunction in Non-ischemic Mice Carotid Arteries.
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Puertas-Umbert L, Puig N, Camacho M, Dantas AP, Marín R, Martí-Fàbregas J, Jiménez-Xarrié E, Benitez S, Camps-Renom P, and Jiménez-Altayó F
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- Humans, Male, Mice, Animals, Infant, Prostaglandin-Endoperoxide Synthases, Constriction, Pathologic complications, Carotid Arteries, Risk Factors, Carotid Stenosis complications, Stroke complications, Atherosclerosis complications
- Abstract
Atherosclerosis is responsible for 20% of ischemic strokes, and severe carotid stenosis is associated with a higher incidence of first-ever and recurrent strokes. The release of pro-inflammatory mediators into the blood in severe atherosclerosis may aggravate endothelial dysfunction after stroke contributing to impair disease outcomes. We hypothesize that environments of severe carotid atherosclerotic disease worsen endothelial dysfunction in stroke linked to enhanced risk of further cerebrovascular events. We mounted nonischemic common carotid arteries from 2- to 4-month-old male Oncins France 1 mice in tissue baths for isometric contraction force measurements and exposed them to serum from men with a recent ischemic stroke and different degrees of carotid stenosis: low- or moderate-grade stenosis (LMGS; < 70%) and high-grade stenosis (HGS; ≥ 70%). The results show that serum from stroke patients induced an impairment of acetylcholine relaxations in mice carotid arteries indicative of endothelium dysfunction. This effect was more pronounced after incubation with serum from patients with a recurrent stroke or vascular death within 1 year of follow-up. When patients were stratified according to the degree of stenosis, serum from HGS patients induced more pronounced carotid artery endothelial dysfunction, an effect that was associated with enhanced circulating levels of IL-1β. Mechanistically, endothelial dysfunction was prevented by both nonselective and selective COX blockade. Altogether, the present findings add knowledge on the understanding of the mechanisms involved in the increased risk of stroke in atherosclerosis and suggest that targeting COX in the carotid artery wall may represent a potential novel therapeutic strategy for secondary stroke prevention., (© 2022. The Author(s).)
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- 2024
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16. Evidence for the involvement of TRPV2 channels in the modulation of vascular tone in the mouse aorta.
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Perálvarez-Marín A, Solé M, Serrano J, Taddeucci A, Pérez B, Penas C, Manich G, Jiménez M, D'Ocon P, and Jiménez-Altayó F
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- Mice, Rats, Male, Animals, Mechanotransduction, Cellular, Aorta metabolism, Vasodilation, Adenosine Triphosphate metabolism, Endothelium, Vascular physiology, Endothelial Cells, Probenecid pharmacology
- Abstract
Aims: Transient receptor potential vanilloid 2 (TRPV2) channels are expressed in both smooth muscle and endothelial cells and participate in vascular mechanotransduction and sensing of high temperatures and lipids. Nevertheless, the impact of TRPV2 channel activation by agonists on the coordinated and cell-type specific modulation of vasoreactivity is unknown., Main Methods: Aorta from 2- to 4-months-old male Oncins France 1 mice was dissected and mounted in tissue baths for isometric tension measurements. TRPV2 channel expression was assessed by immunofluorescence and western blot in mice aortas and in cultured A7r5 rat aortic smooth muscle cells., Key Findings: TRPV2 channels were expressed in all three mouse aorta layers. Activation of TRPV2 channels with probenecid evoked endothelium-dependent relaxations through a mechanism that involved activation of smooth muscle K
ir and Kv channels. In addition, TRPV2 channel inhibition with tranilast increased endothelium-independent relaxations to probenecid and this effect was abrogated by the KATP channel blocker glibenclamide, revealing that smooth muscle TRPV2 channels induce negative feedback on probenecid relaxations mediated via KATP channel inhibition. Exposure to the NO donor sodium nitroprusside increased TRPV2 channel translocation to the plasma membrane in cultured smooth muscle cells and enhanced negative feedback on probenecid relaxations., Significance: In conclusion, we present the first evidence that TRPV2 channels may modulate vascular tone through a balance of opposed inputs from the endothelium and the smooth muscle leading to net vasodilation. The fact that TRPV2 channel-induced activity can be amplified by NO emphasizes the pathophysiological relevance of these findings., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be interpreted as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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17. Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold.
- Author
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Catalina-Hernández È, López-Martín M, Masnou-Sánchez D, Martins M, Lorenz-Fonfria VA, Jiménez-Altayó F, Hellmich UA, Inada H, Alcaraz A, Furutani Y, Nonell-Canals A, Vázquez-Ibar JL, Domene C, Gaudet R, and Perálvarez-Marín A
- Abstract
TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca
2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target., Competing Interests: None., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)- Published
- 2023
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18. Targeting mitochondrial stress with Szeto-Schiller 31 prevents experimental abdominal aortic aneurysm: Crosstalk with endoplasmic reticulum stress.
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Navas-Madroñal M, Almendra-Pegueros R, Puertas-Umbert L, Jiménez-Altayó F, Julve J, Pérez B, Consegal-Pérez M, Kassan M, Martínez-González J, Rodriguez C, and Galán M
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- Mice, Animals, Reactive Oxygen Species metabolism, Aorta, Abdominal, Endoplasmic Reticulum Stress, Mitochondria metabolism, Apolipoproteins E metabolism, Inflammation drug therapy, Inflammation metabolism, Angiotensin II metabolism, Disease Models, Animal, Mice, Inbred C57BL, Mice, Knockout, Aortic Aneurysm, Abdominal chemically induced, Aortic Aneurysm, Abdominal prevention & control, Aortic Aneurysm, Abdominal metabolism
- Abstract
Background and Purpose: Mitochondrial dysfunction and inflammation contribute to a myriad of cardiovascular diseases. Deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is involved in the development of vascular diseases. This study determined if inhibition of mitochondrial stress reduces aneurysm development in angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE
-/- ) mice and its effect on ER stress., Experimental Approach: The mitochondria-targeted tetrapeptide, Szeto-Schiller 31 (SS31), ameliorated mitochondrial dysfunction and the enhanced expression of ER stress markers triggered by Ang II in ApoE-/- mice, and limited plasmatic and vascular reactive oxygen species (ROS) levels. Interestingly, SS31 improved survival, reduced the incidence and severity of abdominal aortic aneurysm (AAA), and the Ang II-induced increase in aortic diameter as evaluated by ultrasonography, resembling the response triggered by the classic ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (PBA)., Key Results: Disorganization of the extracellular matrix, increased expression of metalloproteinases and pro-inflammatory markers and infiltration of immune cells induced by Ang II in the abdominal aorta were effectively reduced by SS31 and ER inhibitors. Further, C/EBP homologous protein (CHOP) deficiency in ApoE-/- mice attenuated Ang II-mediated increase in vascular diameter and incidence of AAA, suggesting its contribution to the favourable response induced by ER stress inhibition., Conclusions and Implications: Our data demonstrate that inhibition of mitochondrial stress by SS31 limits AAA formation and increases survival through a reduction of vascular remodelling, inflammation and ROS, and support that attenuation of ER stress contributes to the favourable response elicited by SS31., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
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19. Novel pharmacological approaches in abdominal aortic aneurysm.
- Author
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Puertas-Umbert L, Almendra-Pegueros R, Jiménez-Altayó F, Sirvent M, Galán M, Martínez-González J, and Rodríguez C
- Subjects
- Humans, Aorta, Abdominal pathology, Doxycycline therapeutic use, Aortic Aneurysm, Abdominal drug therapy, Aortic Aneurysm, Abdominal pathology, Aortic Rupture drug therapy, Aortic Rupture prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA., (© 2023 The Author(s).)
- Published
- 2023
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20. Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome.
- Author
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Rodríguez-Rovira I, López-Sainz A, Palomo-Buitrago ME, Pérez B, Jiménez-Altayó F, Campuzano V, and Egea G
- Subjects
- Mice, Male, Animals, Antioxidants, Disease Models, Animal, Allantoin, Marfan Syndrome complications, Marfan Syndrome pathology, Hyperuricemia complications, Aortic Aneurysm complications
- Abstract
Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice ( Fbn1
C1041G/+ ) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice., Competing Interests: The authors declare no conflict of interest.- Published
- 2023
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21. Electronegative LDL Is Associated with Plaque Vulnerability in Patients with Ischemic Stroke and Carotid Atherosclerosis.
- Author
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Puig N, Camps-Renom P, Solé A, Aguilera-Simón A, Jiménez-Xarrié E, Fernández-León A, Camacho M, Guasch-Jiménez M, Marin R, Martí-Fàbregas J, Martínez-Domeño A, Prats-Sánchez L, Casoni F, Pérez B, Jiménez-Altayó F, Sánchez-Quesada JL, and Benitez S
- Abstract
Owing to the high risk of recurrence, identifying indicators of carotid plaque vulnerability in atherothrombotic ischemic stroke is essential. In this study, we aimed to identify modified LDLs and antioxidant enzymes associated with plaque vulnerability in plasma from patients with a recent ischemic stroke and carotid atherosclerosis. Patients underwent an ultrasound, a CT-angiography, and an
18 F-FDG PET. A blood sample was obtained from patients (n = 64, 57.8% with stenosis ≥50%) and healthy controls (n = 24). Compared to the controls, patients showed lower levels of total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB), apoA-I, apoA-II, and apoE, and higher levels of apoJ. Patients showed lower platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase-1 (PON-1) enzymatic activities in HDL, and higher plasma levels of oxidized LDL (oxLDL) and electronegative LDL (LDL(-)). The only difference between patients with stenosis ≥50% and <50% was the proportion of LDL(-). In a multivariable logistic regression analysis, the levels of LDL(-), but not of oxLDL, were independently associated with the degree of carotid stenosis (OR: 5.40, CI: 1.15-25.44, p < 0.033), the presence of hypoechoic plaque (OR: 7.52, CI: 1.26-44.83, p < 0.027), and of diffuse neovessels (OR: 10.77, CI: 1.21-95.93, p < 0.033), indicating that an increased proportion of LDL(-) is associated with vulnerable atherosclerotic plaque.- Published
- 2023
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22. Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress.
- Author
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Rodríguez-Rovira I, Arce C, De Rycke K, Pérez B, Carretero A, Arbonés M, Teixidò-Turà G, Gómez-Cabrera MC, Campuzano V, Jiménez-Altayó F, and Egea G
- Subjects
- Mice, Animals, Allopurinol pharmacology, Reactive Oxygen Species metabolism, Hydrogen Peroxide metabolism, Aorta metabolism, Disease Models, Animal, Oxidative Stress, Oxidation-Reduction, Marfan Syndrome metabolism, Aortic Aneurysm drug therapy, Aortic Aneurysm genetics, Aortic Aneurysm prevention & control
- Abstract
Background: Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy., Methods and Results: In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1
C1041G/+ ), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3'-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2 O2 , and NOX4 and MMP2 transcriptional overexpression., Conclusions: Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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23. Plasma sICAM-1 as a Biomarker of Carotid Plaque Inflammation in Patients with a Recent Ischemic Stroke.
- Author
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Puig N, Camps-Renom P, Camacho M, Aguilera-Simón A, Jiménez-Altayó F, Fernández-León A, Marín R, Martí-Fàbregas J, Sánchez-Quesada JL, Jiménez-Xarrié E, and Benitez S
- Subjects
- Biomarkers, Fluorodeoxyglucose F18, Humans, Inflammation complications, Intercellular Adhesion Molecule-1, Positron-Emission Tomography, Prospective Studies, Carotid Stenosis complications, Carotid Stenosis diagnostic imaging, Ischemic Stroke, Plaque, Atherosclerotic complications, Plaque, Atherosclerotic diagnostic imaging, Stroke complications
- Abstract
18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET) identifies carotid plaque inflammation and predicts stroke recurrence in patients with atherothrombotic stroke. The aim of the study was to identify plasma inflammatory biomarkers associated with plaque inflammation according to18 F-FDG uptake. We conducted a prospective study of consecutive adult patients with a recent (< 7 days) anterior circulation ischemic stroke and at least one atherosclerotic plaque in the ipsilateral internal carotid artery. We included 64 patients, 57.8% of whom showed a carotid stenosis ≥ 50%. All patients underwent an early (< 15 days from inclusion)18 F-FDG PET, and a blood sample was obtained at days 7 ± 1 from the stroke. The plasma concentration of 16 inflammation-related molecules was analyzed in a Luminex using xMAP technology. Multivariable linear regression was used to assess the association between plasma biomarkers and the standardized uptake value (SUV) of18 F-FDG uptake. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and fractalkine (FKN) were independently associated with plaque inflammation (β = 0.121, 95% CI 0.061-0.181, p < 0.001; β = 0.144, 95% CI 0.012-0.276, p = 0.033; β = 0.136, 95% CI 0.037-0.235, p = 0.008). In a multivariable logistic regression analysis, sICAM-1 was associated with SUVmax ≥ 2.85 (OR = 1.02, 95% CI 1.00-1.03, p = 0.020). Multivariable Cox regression was used to assess the association between biomarkers and stroke recurrence. sICAM-1 was associated with stroke recurrence (HR = 1.03, 95% CI 1.00-1.05, p = 0.002). In summary, elevated concentrations of sICAM-1 were associated with carotid plaque inflammation and an increased risk of stroke recurrence in patients with recent ischemic stroke and carotid atherosclerosis., (© 2022. The Author(s).)- Published
- 2022
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24. An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging.
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Jiménez-Altayó F, Cabrera A, Bagán A, Giménez-Llort L, D'Ocon P, Pérez B, Pallàs M, and Escolano C
- Abstract
Imidazoline receptors (IR) are classified into three receptor subtypes (I
1 R, I2 R, and I3 R) and previous studies showed that regulation of I2 R signaling has neuroprotective potential. In order to know if I2 R has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized I2 R ligands, diethyl (1RS,3aSR,6aSR)-5-(3-chloro-4-fluorophenyl)-4,6-dioxo-1-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole -1-phosphonate (B06) and diethyl [(1-(3-chloro-4-fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazol-4-yl]phosphonate] (MCR5). Thoracic aortas from Oncins France 1 (3- to 4-months-old) and C57BL/6 (3- to 4- and 16- to 17-months-old mice) were mounted in tissue baths to measure isometric tension. In young mice of both strains, MCR5 induced greater relaxations than either B06 or the high-affinity I2 R selective ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI), which evoked marginal responses. MCR5 relaxations were independent of I2 R, as IR ligands did not significantly affect them, involved activation of smooth muscle KATP channels and inhibition of L-type voltage-gated Ca2+ channels, and were only slightly modulated by endothelium-derived nitric oxide (negatively) and prostacyclin (positively). Notably, despite the presence of endothelial dysfunction in old mice, MCR5 relaxations were preserved. In conclusion, the present study provides evidence against a functional contribution of I2 R in the modulation of vascular tone in the mouse aorta. Moreover, the I2 R ligand MCR5 is an endothelium-independent vasodilator that acts largely via I2 R-independent pathways and is resistant to aging. We propose MCR5 as a candidate drug for the management of vascular disease in the elderly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiménez-Altayó, Cabrera, Bagán, Giménez-Llort, D’Ocon, Pérez, Pallàs and Escolano.)- Published
- 2022
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25. Molecular Mechanisms Underlying the Effects of Olive Oil Triterpenic Acids in Obesity and Related Diseases.
- Author
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Claro-Cala CM, Jiménez-Altayó F, Zagmutt S, and Rodriguez-Rodriguez R
- Subjects
- Humans, Obesity drug therapy, Olive Oil pharmacology, Diet, Mediterranean, Metabolic Syndrome drug therapy, Oleanolic Acid pharmacology, Oleanolic Acid therapeutic use
- Abstract
Dietary components exert protective effects against obesity and related metabolic and cardiovascular disturbances by interfering with the molecular pathways leading to these pathologies. Dietary biomolecules are currently promising strategies to help in the management of obesity and metabolic syndrome, which are still unmet medical issues. Olive oil, a key component of the Mediterranean diet, provides an exceptional lipid matrix highly rich in bioactive molecules. Among them, the pentacyclic triterpenic acids (i.e., oleanolic acid) have gained clinical relevance in the last decade due to their wide range of biological actions, particularly in terms of vascular function, obesity and insulin resistance. Considering the promising effects of these triterpenic compounds as nutraceuticals and components of functional foods against obesity and associated complications, the aim of our review is to decipher and discuss the main molecular mechanisms underlying these effects driven by olive oil triterpenes, in particular by oleanolic acid. Special attention is paid to their signaling and targets related to glucose and insulin homeostasis, lipid metabolism, adiposity and cardiovascular dysfunction in obesity. Our study is aimed at providing a better understanding of the impact of dietary components of olive oil in the long-term management of obesity and metabolic syndrome in humans.
- Published
- 2022
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26. Arachnoid membrane as a source of sphingosine-1-phosphate that regulates mouse middle cerebral artery tone.
- Author
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Jiménez-Altayó F, Marzi J, Galan M, Dantas AP, Ortega M, Rojas S, Egea G, Schenke-Layland K, Jiménez-Xarrié E, and Planas AM
- Subjects
- Animals, Female, Hydrazones pharmacology, Lysophospholipids genetics, Male, Mice, Mice, Knockout, Phosphotransferases (Alcohol Group Acceptor) deficiency, Phosphotransferases (Alcohol Group Acceptor) metabolism, Sphingosine genetics, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors antagonists & inhibitors, Sphingosine-1-Phosphate Receptors genetics, Arachnoid metabolism, Lysophospholipids metabolism, Middle Cerebral Artery metabolism, Signal Transduction, Sphingosine analogs & derivatives, Sphingosine-1-Phosphate Receptors metabolism, Vasoconstriction
- Abstract
Growing evidence indicates that perivascular tissue is critical to modulate vessel function. We hypothesized that the arachnoid membrane surrounding middle cerebral artery (MCA) regulates its function via sphingosine-1-phosphate (S1P)-induced vasoconstriction. The MCA from 3- to 9-month-old male and female wild-type (Oncine France 1 and C57BL/6) mice and sphingosine kinase 2 knockout (SphK2-/-) mice in the C57BL/6 background was mounted in pressure myographs with and without arachnoid membrane. Raman microspectroscopy and imaging were used for in situ detection of S1P. The presence of arachnoid tissue was associated with reduced external and lumen MCA diameters, and with an increase in basal tone regardless of sex and strain background. Strong S1P-positive signals were detected in the arachnoid surrounding the MCA wall in both mice models, as well as in a human post-mortem specimen. Selective S1P receptor 3 antagonist TY 52156 markedly reduced both MCA vasoconstriction induced by exogenous S1P and arachnoid-dependent basal tone increase. Compared to 3-month-old mice, the arachnoid-mediated contractile influence persisted in 9-month-old mice despite a decline in arachnoid S1P deposits. Genetic deletion of SphK2 decreased arachnoid S1P content and vasoconstriction. This is the first experimental evidence that arachnoid membrane regulates the MCA tone mediated by S1P.
- Published
- 2022
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27. Anti-TGFβ (Transforming Growth Factor β) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome.
- Author
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Arce C, Rodríguez-Rovira I, De Rycke K, Durán K, Campuzano V, Fabregat I, Jiménez-Altayó F, Berraondo P, and Egea G
- Subjects
- Animals, Aorta pathology, Aortic Aneurysm genetics, Aortic Aneurysm metabolism, Aortic Aneurysm pathology, Dependovirus genetics, Dilatation, Pathologic, Disease Models, Animal, Female, Fibrillin-1 genetics, Genetic Vectors, Male, Marfan Syndrome genetics, Mice, Inbred C57BL, Peptide Fragments genetics, Proteoglycans genetics, Receptors, Transforming Growth Factor beta genetics, Signal Transduction, Transforming Growth Factor beta genetics, Mice, Aorta metabolism, Aortic Aneurysm prevention & control, Gene Transfer Techniques, Genetic Therapy, Marfan Syndrome complications, Peptide Fragments metabolism, Proteoglycans metabolism, Receptors, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta metabolism
- Abstract
Objective: We investigated the effect of a potent TGFβ (transforming growth factor β) inhibitor peptide (P144) from the betaglycan/TGFβ receptor III on aortic aneurysm development in a Marfan syndrome mouse model., Approach and Results: We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFβ signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfβ1 and Tgfβ2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFβ signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfβ1 and Tgfβ2 mRNA levels., Conclusions: P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFβ signaling during the early stages of aortic disease progression.
- Published
- 2021
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28. Anti-inflammatory and sedative activities of Peperomia galioides : in vivo studies in mice.
- Author
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Wilches I, Jiménez-Castillo P, Cuzco N, Clos MV, Jiménez-Altayó F, Peñaherrera E, Jerves-Andrade L, Tobar V, Vander Heyden Y, Leon-Tamariz F, and Vila E
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Croton Oil toxicity, Edema chemically induced, Edema drug therapy, Hypnotics and Sedatives chemistry, Inflammation chemically induced, Inflammation drug therapy, Male, Mice, Peroxidase metabolism, Plant Extracts chemistry, Plant Leaves chemistry, Plants, Medicinal chemistry, Sleep drug effects, Tumor Necrosis Factor-alpha blood, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Hypnotics and Sedatives pharmacology, Peperomia chemistry, Plant Extracts pharmacology
- Abstract
Aerial parts (leaves, flowers, stem) of Peperomia galioides extract administered to mice, was used to confirm its anti-inflammatory and sedative folk uses. The anti-inflammatory activity was assessed by croton oil-induced ear oedema and myeloperoxidase (acute inflammation); cotton pellet-induced granuloma (sub-acute inflammation) and Escherichia coli Lipopolysaccharide (LPS) induced inflammation (cellular mediators). The sedative activity was studied by the pentobarbital-induced sleeping time test. Single doses (300 and 600 mg/kg; i.p.) of the extract reduced croton oil-induced ear oedema and myeloperoxidase activity. Six days administration of the extract (300 mg/kg, i.p.) to mice implanted with cotton pellets diminished granuloma formation. LPS (20 mg/kg, i.p.) enhanced plasma nitrites and TNF-α levels that were inhibited by the extract. The duration but not the onset of sleeping time was enhanced by 300 and 600 mg/kg of the extract. Our results show that P. galioides has anti-inflammatory and sedative activities in mice, which validates its traditional use.
- Published
- 2021
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29. Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging.
- Author
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Muntsant A, Jiménez-Altayó F, Puertas-Umbert L, Jiménez-Xarrie E, Vila E, and Giménez-Llort L
- Abstract
Life expectancy decreases with aging, with cardiovascular, mental health, and neurodegenerative disorders strongly contributing to the total disability-adjusted life years. Interestingly, the morbidity/mortality paradox points to females having a worse healthy life expectancy. Since bidirectional interactions between cardiovascular and Alzheimer's diseases (AD) have been reported, the study of this emerging field is promising. In the present work, we further explored the cardiovascular-brain interactions in mice survivors of two cohorts of non-transgenic and 3xTg-AD mice, including both sexes, to investigate the frailty/survival through their life span. Survival, monitored from birth, showed exceptionally worse mortality rates in females than males, independently of the genotype. This mortality selection provided a "survivors" cohort that could unveil brain-cardiovascular interaction mechanisms relevant for normal and neurodegenerative aging processes restricted to long-lived animals. The results show sex-dependent distinct physical (worse in 3xTg-AD males), neuropsychiatric-like and cognitive phenotypes (worse in 3xTg-AD females), and hypothalamic-pituitary-adrenal (HPA) axis activation (higher in females), with higher cerebral blood flow and improved cardiovascular phenotype in 3xTg-AD female mice survivors. The present study provides an experimental scenario to study the suggested potential compensatory hemodynamic mechanisms in end-of-life dementia, which is sex-dependent and can be a target for pharmacological and non-pharmacological interventions.
- Published
- 2021
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30. The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature.
- Author
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Costa TJ, Barros PR, Arce C, Santos JD, da Silva-Neto J, Egea G, Dantas AP, Tostes RC, and Jiménez-Altayó F
- Subjects
- Antioxidants pharmacology, Homeostasis, Hydrogen Peroxide, Oxidation-Reduction, Reactive Oxygen Species, Nitric Oxide, Superoxides
- Abstract
Reactive oxygen and nitrogen species are produced in a wide range of physiological reactions that, at low concentrations, play essential roles in living organisms. There is a delicate equilibrium between formation and degradation of these mediators in a healthy vascular system, which contributes to maintaining these species under non-pathological levels to preserve normal vascular functions. Antioxidants scavenge reactive oxygen and nitrogen species to prevent or reduce damage caused by excessive oxidation. However, an excessive reductive environment induced by exogenous antioxidants may disrupt redox balance and lead to vascular pathology. This review summarizes the main aspects of free radical biochemistry (formation, sources and elimination) and the crucial actions of some of the most biologically relevant and well-characterized reactive oxygen and nitrogen species (hydrogen peroxide, superoxide anion and nitric oxide) in the physiological regulation of vascular function, structure and angiogenesis. Furthermore, current preclinical and clinical evidence is discussed on how excessive removal of these crucial responses by exogenous antioxidants (vitamins and related compounds, polyphenols) may perturb vascular homeostasis. The aim of this review is to provide information of the crucial physiological roles of oxidation in the endothelium, vascular smooth muscle cells and perivascular adipose tissue for developing safer and more effective vascular interventions with antioxidants., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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31. Uric Acid Treatment After Stroke Prevents Long-Term Middle Cerebral Artery Remodelling and Attenuates Brain Damage in Spontaneously Hypertensive Rats.
- Author
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Jiménez-Xarrié E, Pérez B, Dantas AP, Puertas-Umbert L, Martí-Fabregas J, Chamorro Á, Planas AM, Vila E, and Jiménez-Altayó F
- Subjects
- Animals, Antioxidants administration & dosage, Brain Injuries diagnostic imaging, Hypertension diagnostic imaging, Infarction, Middle Cerebral Artery diagnostic imaging, Male, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Treatment Outcome, Vascular Remodeling physiology, Brain Injuries prevention & control, Cerebral Revascularization methods, Hypertension drug therapy, Infarction, Middle Cerebral Artery drug therapy, Uric Acid administration & dosage, Vascular Remodeling drug effects
- Abstract
Hypertension is the most important modifiable risk factor for stroke and is associated with poorer post-stroke outcomes. The antioxidant uric acid is protective in experimental normotensive ischaemic stroke. However, it is unknown whether this treatment exerts long-term protection in hypertension. We aimed to evaluate the impact of transient intraluminal middle cerebral artery (MCA) occlusion (90 min)/reperfusion (1-15 days) on brain and vascular damage progression in adult male Wistar-Kyoto (WKY; n = 36) and spontaneously hypertensive (SHR; n = 37) rats treated (i.v./120 min post-occlusion) with uric acid (16 mg kg
-1 ) or vehicle (Locke's buffer). Ischaemic brain damage was assessed longitudinally with magnetic resonance imaging and properties of MCA from both hemispheres were studied 15 days after stroke. Brain lesions in WKY rats were associated with a transitory increase in circulating IL-18 and cerebrovascular oxidative stress that did not culminate in long-term MCA alterations. In SHR rats, more severe brain damage and poorer neurofunctional outcomes were coupled to higher cortical cerebral blood flow at the onset of reperfusion, a transient increase in oxidative stress and long-lasting stroke-induced MCA hypertrophic remodelling. Thus, stroke promotes larger brain and vascular damage in hypertensive rats that persists for long-time. Uric acid administered during early reperfusion attenuated short- and long-term brain injuries in both normotensive and hypertensive rats, an effect that was associated with abolishment of the acute oxidative stress response and prevention of stroke-induced long-lasting MCA remodelling in hypertension. These results suggest that uric acid might be an effective strategy to improve stroke outcomes in hypertensive subjects.- Published
- 2020
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32. Small Resistance Artery Disease and ACE2 in Hypertension: A New Paradigm in the Context of COVID-19.
- Author
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Galán M and Jiménez-Altayó F
- Abstract
Cardiovascular disease causes almost one third of deaths worldwide, and more than half are related to primary arterial hypertension (PAH). The occurrence of several deleterious events, such as hyperactivation of the renin-angiotensin system (RAS), and oxidative and inflammatory stress, contributes to the development of small vessel disease in PAH. Small resistance arteries are found at various points through the arterial tree, act as the major site of vascular resistance, and actively regulate local tissue perfusion. Experimental and clinical studies demonstrate that alterations in small resistance artery properties are important features of PAH pathophysiology. Diseased small vessels in PAH show decreased lumens, thicker walls, endothelial dysfunction, and oxidative stress and inflammation. These events may lead to altered blood flow supply to tissues and organs, and can increase the risk of thrombosis. Notably, PAH is prevalent among patients diagnosed with COVID-19, in whom evidence of small vessel disease leading to cardiovascular pathology is reported. The SARS-Cov2 virus, responsible for COVID-19, achieves cell entry through an S (spike) high-affinity protein binding to the catalytic domain of the angiotensin-converting enzyme 2 (ACE2), a negative regulator of the RAS pathway. Therefore, it is crucial to examine the relationship between small resistance artery disease, ACE2, and PAH, to understand COVID-19 morbidity and mortality. The scope of the present review is to briefly summarize available knowledge on the role of small resistance artery disease and ACE2 in PAH, and critically discuss their clinical relevance in the context of cardiovascular pathology associated to COVID-19., (Copyright © 2020 Galán and Jiménez-Altayó.)
- Published
- 2020
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33. Reactive Oxygen Species and Oxidative Stress in the Pathogenesis and Progression of Genetic Diseases of the Connective Tissue.
- Author
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Egea G, Jiménez-Altayó F, and Campuzano V
- Abstract
Connective tissue is known to provide structural and functional "glue" properties to other tissues. It contains cellular and molecular components that are arranged in several dynamic organizations. Connective tissue is the focus of numerous genetic and nongenetic diseases. Genetic diseases of the connective tissue are minority or rare, but no less important than the nongenetic diseases. Here we review the impact of reactive oxygen species (ROS) and oxidative stress on the onset and/or progression of diseases that directly affect connective tissue and have a genetic origin. It is important to consider that ROS and oxidative stress are not synonymous, although they are often closely linked. In a normal range, ROS have a relevant physiological role, whose levels result from a fine balance between ROS producers and ROS scavenge enzymatic systems. However, pathology arises or worsens when such balance is lost, like when ROS production is abnormally and constantly high and/or when ROS scavenge (enzymatic) systems are impaired. These concepts apply to numerous diseases, and connective tissue is no exception. We have organized this review around the two basic structural molecular components of connective tissue: The ground substance and fibers (collagen and elastic fibers).
- Published
- 2020
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34. Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages.
- Author
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Puig N, Montolio L, Camps-Renom P, Navarra L, Jiménez-Altayó F, Jiménez-Xarrié E, Sánchez-Quesada JL, and Benitez S
- Subjects
- Humans, Inflammation chemically induced, Lipoproteins, LDL adverse effects, Macrophages immunology, Triglycerides adverse effects
- Abstract
Electronegative low-density lipoprotein (LDL) (LDL(-)), a modified LDL that is present in blood and exerts atherogenic effects on endothelial cells and monocytes. This study aimed to determine the action of LDL(-) on monocytes differentiated into macrophages. LDL(-) and in vitro-modified LDLs (oxidized, aggregated, and acetylated) were added to macrophages derived from THP1 monocytes over-expressing CD14 (THP1-CD14). Then, cytokine release, cell differentiation, lipid accumulation, and gene expression were measured by ELISA, flow cytometry, thin-layer chromatography, and real-time PCR, respectively. LDL(-) induced more cytokine release in THP1-CD14 macrophages than other modified LDLs. LDL(-) also promoted morphological changes ascribed to differentiated macrophages. The addition of high-density lipoprotein (HDL) and anti-TLR4 counteracted these effects. LDL(-) was highly internalized by macrophages, and it was the major inductor of intracellular lipid accumulation in triglyceride-enriched lipid droplets. In contrast to inflammation, the addition of anti-TLR4 had no effect on lipid accumulation, thus suggesting an uptake pathway alternative to TLR4. In this regard, LDL(-) upregulated the expression of the scavenger receptors CD36 and LOX-1, as well as several genes involved in triglyceride (TG) accumulation. The importance and novelty of the current study is that LDL(-), a physiologically modified LDL, exerted atherogenic effects in macrophages by promoting differentiation, inflammation, and triglyceride-enriched lipid droplets formation in THP1-CD14 macrophages, probably through different receptors.
- Published
- 2020
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35. Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome.
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Jiménez-Altayó F, Ortiz-Romero P, Puertas-Umbert L, Dantas AP, Pérez B, Vila E, D'Ocon P, and Campuzano V
- Subjects
- Animals, Aorta, Thoracic drug effects, Aorta, Thoracic metabolism, Aortic Stenosis, Supravalvular physiopathology, Disease Models, Animal, Elastin metabolism, Endothelium, Vascular physiology, Ethidium analogs & derivatives, Ethidium blood, Male, Mice, Mutant Strains, Nitric Oxide metabolism, Nitric Oxide Synthase Type I metabolism, Oxidative Stress, Phenylephrine pharmacology, Receptors, Adrenergic, alpha-1 genetics, Williams Syndrome genetics, Williams Syndrome metabolism, Aorta, Thoracic physiopathology, Receptors, Adrenergic, alpha-1 metabolism, Williams Syndrome physiopathology
- Abstract
Williams-Beuren syndrome (WBS) is a rare disorder caused by a heterozygous deletion of 26-28 contiguous genes that affects the brain and cardiovascular system. Here, we investigated whether WBS affects aortic structure and function in the complete deletion (CD) mouse model harbouring the most common deletion found in WBS patients. Thoracic aortas from 3-4 months-old male CD mice and wild-type littermates were mounted in wire myographs or were processed for histomorphometrical analysis. Nitric oxide synthase (NOS) isoforms and oxidative stress levels were assessed. Ascending aortas from young adult CD mice showed moderate (50%) luminal stenosis, whereas endothelial function and oxidative stress were comparable to wild-type. CD mice showed greater contractions to KCl. However, α1-adrenergic contractions to phenylephrine, but not with a thromboxane analogue, were compromised. Decreased phenylephrine responses were not affected by selective inducible NOS blockade with 1400 W, but were prevented by the non-selective NOS inhibitor L-NAME and the selective neuronal NOS inhibitor SMTC. Consistently, CD mice showed increased neuronal NOS expression in aortas. Overall, aortic stenosis in CD mice coexists with excessive nNOS-derived NO signaling that compromises ascending aorta α1-adrenergic contractions. We suggest that increased neuronal NOS signaling may act as a physiological 'brake' against the detrimental effects of stenosis.
- Published
- 2020
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36. Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ERα36.
- Author
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Costa TJ, Jiménez-Altayó F, Echem C, Akamine EH, Tostes R, Vila E, Dantas AP, and Carvalho MHC
- Subjects
- Animals, Carotid Arteries metabolism, Estrogens therapeutic use, Female, Gene Expression Regulation, Mice, Aging, Carotid Arteries physiopathology, Estrogen Receptor alpha genetics, Estrogens adverse effects, Prostaglandins metabolism, Vasoconstriction
- Abstract
Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women's age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17β-estradiol starting at the day of ovariectomy (early-onset, E
2 E) or 45 days after surgery (late-onset, E2 L). In SAMR1, both treatments, E2 E and E2 L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2 E: 128.1 ± 11.6; E2 L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2 E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2 L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2 E: 183.3 ± 11.1; E2 L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2 L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2 L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results- Published
- 2019
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37. Uric acid treatment after stroke modulates the Krüppel-like factor 2-VEGF-A axis to protect brain endothelial cell functions: Impact of hypertension.
- Author
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Vila E, Solé M, Masip N, Puertas-Umbert L, Amaro S, Dantas AP, Unzeta M, D'Ocon P, Planas AM, Chamorro Á, and Jiménez-Altayó F
- Subjects
- Animals, Antioxidants pharmacology, Antioxidants therapeutic use, Biomarkers blood, Blood-Brain Barrier drug effects, Brain drug effects, Brain metabolism, Cell Line, Double-Blind Method, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Humans, Hypertension drug therapy, Hypertension pathology, Kruppel-Like Transcription Factors agonists, Male, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Stroke drug therapy, Stroke pathology, Treatment Outcome, Uric Acid pharmacology, Vascular Endothelial Growth Factor A antagonists & inhibitors, Blood-Brain Barrier metabolism, Hypertension blood, Kruppel-Like Transcription Factors blood, Stroke blood, Uric Acid therapeutic use, Vascular Endothelial Growth Factor A blood
- Abstract
Uric acid (UA) is a promising protective treatment in ischaemic stroke, but the precise molecular targets underlying its in vivo beneficial actions remain unclear. High concentrations of UA inhibit angiogenesis of cultured endothelial cells via Krüppel-like factor 2 (KLF)-induced downregulation of vascular endothelial growth factor (VEGF), a pro-angiogenic mediator that is able to increase blood-brain barrier (BBB) permeability in acute stroke. Here, we investigated whether UA treatment after ischaemic stroke protects brain endothelial cell functions and modulates the KLF2-VEGF-A axis. Transient intraluminal middle cerebral artery (MCA) occlusion/reperfusion was induced in adult male spontaneously hypertensive (SHR) rats and corresponding normotensive Wistar-Kyoto (WKY) rats. Animals received UA (16 mg/kg) or vehicle (Locke's buffer) i.v. at reperfusion. BBB permeability was evaluated by Evans blue extravasation to the brain and in human cerebral endothelial hCMEC/D3 cells under oxygen-glucose deprivation/re-oxygenation. Circulating VEGF-A levels were measured in rats and acute ischaemic stroke patients from the URICO-ICTUS trial. Angiogenesis progression was assessed in Matrigel-cultured MCA. Worse post-stroke brain damage in SHR than WKY rats was associated with higher hyperaemia at reperfusion, increased Evans blue extravasation, exacerbated MCA angiogenic sprouting, and higher VEGF-A levels. UA treatment reduced infarct volume and Evans blue leakage in both rat strains, improved endothelial cell barrier integrity and KLF2 expression, and lowered VEGF-A levels in SHR rats. Hypertensive stroke patients treated with UA showed lower levels of VEGF-A than patients receiving vehicle. Consistently, UA prevented the enhanced MCA angiogenesis in SHR rats by a mechanism involving KLF2 activation. We conclude that UA treatment after ischaemic stroke upregulates KLF2, reduces VEGF-A signalling, and attenuates brain endothelial cell dysfunctions leading to neuroprotection., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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38. Uric acid therapy for vasculoprotection in acute ischemic stroke.
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Amaro S, Jiménez-Altayó F, and Chamorro Á
- Abstract
Uric acid (UA) is a product of the catabolism of purine nucleotides, the principal constituents of DNA, RNA, and cellular energy stores, such as adenosine triphosphate. The main properties of UA include scavenging of hydroxyl radicals, superoxide anion, hydrogen peroxide, and peroxynitrite that make this compound to be the most potent antioxidant in the human plasma. As the result of two silencing mutations in the gene of the hepatic enzyme uricase which degrades UA to allantoin, humans have higher levels of UA than most mammals. However, these levels rapidly decrease following an acute ischemic stroke (AIS), and this decrement has been associated to worse stroke outcomes. This review highlights the safety and potential clinical value of UA therapy in AIS, particularly in patients more exposed to redox-mediated mechanism following the onset of ischemia, such as women, hyperglycemic patients, or patients treated with mechanical thrombectomy. The clinical findings are supported by preclinical data gathered in different laboratories, and in assorted animal species which include male and female individuals or animals harboring comorbidities frequently encountered in patients with AIS, such as hyperglycemia or hypertension. A remarkable finding in these studies is that UA targets its main effects in the brain vasculature since available evidence suggests that does not seem to cross the blood-brain barrier. Altogether, the available data with UA therapy extend the importance of vasculoprotection for effective neuroprotection at the bedside and reinforce the role of endothelial cells after brain ischemia for an increased survival of the whole neurovascular unit., Competing Interests: Dr. Chamorro owns stock in FreeOx Biootech SL.
- Published
- 2019
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39. CD69 Plays a Beneficial Role in Ischemic Stroke by Dampening Endothelial Activation.
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Brait VH, Miró-Mur F, Pérez-de-Puig I, Notario L, Hurtado B, Pedragosa J, Gallizioli M, Jiménez-Altayó F, Arbaizar-Rovirosa M, Otxoa-de-Amezaga A, Monteagudo J, Ferrer-Ferrer M, de la Rosa X, Bonfill-Teixidor E, Salas-Perdomo A, Hernández-Vidal A, Garcia-de-Frutos P, Lauzurica P, and Planas AM
- Subjects
- Animals, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte genetics, Blood Coagulation, Blood Platelets metabolism, Brain pathology, Cells, Cultured, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Disease Models, Animal, Endothelial Cells pathology, Infarction, Middle Cerebral Artery genetics, Infarction, Middle Cerebral Artery pathology, Lectins, C-Type deficiency, Lectins, C-Type genetics, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction, T-Lymphocytes pathology, von Willebrand Factor metabolism, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, Brain blood supply, Brain metabolism, Endothelial Cells metabolism, Infarction, Middle Cerebral Artery metabolism, Lectins, C-Type metabolism, Lymphocyte Activation, T-Lymphocytes metabolism
- Abstract
Rationale: CD69 is an immunomodulatory molecule induced during lymphocyte activation. Following stroke, T-lymphocytes upregulate CD69 but its function is unknown., Objective: We investigated whether CD69 was involved in brain damage following an ischemic stroke., Methods and Results: We used adult male mice on the C57BL/6 or BALB/c backgrounds, including wild-type mice and CD69
-/- mice, and CD69+/+ and CD69-/- lymphocyte-deficient Rag2-/ - mice, and generated chimeric mice. We induced ischemia by transient or permanent middle cerebral artery occlusion. We measured infarct volume, assessed neurological function, and studied CD69 expression, as well as platelet function, fibrin(ogen) deposition, and VWF (von Willebrand factor) expression in brain vessels and VWF content and activity in plasma, and performed the tail-vein bleeding test and the carotid artery ferric chloride-induced thrombosis model. We also performed primary glial cell cultures and sorted brain CD45- CD11b- CD31+ endothelial cells for mRNA expression studies. We blocked VWF by intravenous administration of anti-VWF antibodies. CD69-/- mice showed larger infarct volumes and worse neurological deficits than the wild-type mice after ischemia. This worsening effect was not attributable to lymphocytes or other hematopoietic cells. CD69 deficiency lowered the time to thrombosis in the carotid artery despite platelet function not being affected. Ischemia upregulated Cd69 mRNA expression in brain endothelial cells. CD69-deficiency increased fibrin(ogen) accumulation in the ischemic tissue, and plasma VWF content and activity, and VWF expression in brain vessels. Blocking VWF reduced infarct volume and reverted the detrimental effect of CD69-/- deficiency., Conclusions: CD69 deficiency promotes a prothrombotic phenotype characterized by increased VWF and worse brain damage after ischemic stroke. The results suggest that CD69 acts as a downregulator of endothelial activation.- Published
- 2019
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40. Detrimental Effects of Testosterone Addition to Estrogen Therapy Involve Cytochrome P-450-Induced 20-HETE Synthesis in Aorta of Ovariectomized Spontaneously Hypertensive Rat (SHR), a Model of Postmenopausal Hypertension.
- Author
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Costa TJ, Ceravolo GS, Echem C, Hashimoto CM, Costa BP, Santos-Eichler RA, Oliveira MA, Jiménez-Altayó F, Akamine EH, Dantas AP, and Carvalho MHC
- Abstract
Postmenopausal period has been associated to different symptoms such as hot flashes, vulvovaginal atrophy, hypoactive sexual desire disorder (HSDD) and others. Clinical studies have described postmenopausal women presenting HSDD can benefit from the association of testosterone to conventional hormonal therapy. Testosterone has been linked to development of cardiovascular diseases including hypertension and it also increases cytochrome P -450-induced 20-HETE synthesis which in turn results in vascular dysfunction. However, the effect of testosterone plus estrogen in the cardiovascular system is still very poorly studied. The aim of the present study is to evaluate the role of cytochrome P -450 pathway in a postmenopausal hypertensive female treated with testosterone plus estrogen. For that, hypertensive ovariectomized rats (OVX-SHR) were used as a model of postmenopausal hypertension and four groups were created: SHAM-operated (SHAM), ovariectomized SHR (OVX), OVX treated for 15 days with conjugated equine estrogens [(CEE) 9.6 μg/Kg/day/po] or CEE associated to testosterone [(CEE+T) 2.85 mg/kg/weekly/im]. Phenylephrine-induced contraction and generation of reactive oxygen species (ROS) were markedly increased in aortic rings from OVX-SHR compared to SHAM rats which were restored by CEE treatment. On the other hand, CEE+T abolished vascular effects by CEE and augmented both systolic and diastolic blood pressure of SHR. Treatment of aortic rings with the CYP/20-HETE synthesis inhibitor HET0016 (1 μM) reduced phenylephrine hyperreactivity and the augmented ROS generation in the CEE+T group. These results are paralleled by the increased CYP4F3 protein expression and activity in aortas of CEE+T. In conclusion, we showed that association of testosterone to estrogen therapy produces detrimental effects in cardiovascular system of ovariectomized hypertensive females via CYP4F3/20-HETE pathway. Therefore, our findings support the standpoint that the CYP/20-HETE pathway is an important therapeutic target for the prevention of cardiovascular disease in menopausal women in the presence of high levels of testosterone.
- Published
- 2018
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41. Redox stress in Marfan syndrome: Dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm.
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Jiménez-Altayó F, Meirelles T, Crosas-Molist E, Sorolla MA, Del Blanco DG, López-Luque J, Mas-Stachurska A, Siegert AM, Bonorino F, Barberà L, García C, Condom E, Sitges M, Rodríguez-Pascual F, Laurindo F, Schröder K, Ros J, Fabregat I, and Egea G
- Subjects
- Adult, Animals, Aortic Aneurysm etiology, Female, Humans, Male, Marfan Syndrome complications, Mice, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular metabolism, Oxidation-Reduction, Young Adult, Aortic Aneurysm metabolism, Marfan Syndrome metabolism, Marfan Syndrome pathology, NADPH Oxidase 4 metabolism, Oxidative Stress physiology
- Abstract
Marfan syndrome (MFS) is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix fibrillin-containing microfibrils and dysfunction of TGF-β signaling. Here we identify the molecular targets of redox stress in aortic aneurysms from MFS patients, and investigate the role of NOX4, whose expression is strongly induced by TGF-β, in aneurysm formation and progression in a murine model of MFS. Working models included aortae and cultured vascular smooth muscle cells (VSMC) from MFS patients, and a NOX4-deficient Marfan mouse model (Fbn1
C1039G/+ -Nox4-/- ). Increased tyrosine nitration and reactive oxygen species levels were found in the tunica media of human aortic aneurysms and in cultured VSMC. Proteomic analysis identified nitrated and carbonylated proteins, which included smooth muscle α-actin (αSMA) and annexin A2. NOX4 immunostaining increased in the tunica media of human Marfan aorta and was transcriptionally overexpressed in VSMC. Fbn1C1039G/+ -Nox4-/- mice aortas showed a reduction of fragmented elastic fibers, which was accompanied by an amelioration in the Marfan-associated enlargement of the aortic root. Increase in the contractile phenotype marker calponin in the tunica media of MFS mice aortas was abrogated in Fbn1C1039G/+ -Nox4-/- mice. Endothelial dysfunction evaluated by myography in the Marfan ascending aorta was prevented by the absence of Nox4 or catalase-induced H2 O2 decomposition. We conclude that redox stress occurs in MFS, whose targets are actin-based cytoskeleton members and regulators of extracellular matrix homeostasis. Likewise, NOX4 have an impact in the progression of the aortic dilation in MFS and in the structural organization of the aortic tunica media, the VSMC phenotypic modulation, and endothelial function., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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42. Crosstalk between Peripheral Small Vessel Properties and Anxious-like Profiles: Sex, Genotype, and Interaction Effects in Mice with Normal Aging and 3×Tg-AD mice at Advanced Stages of Disease.
- Author
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Jiménez-Altayó F, Sánchez-Ventura J, Vila E, and Giménez-Llort L
- Subjects
- Aging pathology, Alzheimer Disease pathology, Animals, Anxiety pathology, Disease Models, Animal, Disease Progression, Female, Male, Mesenteric Arteries pathology, Mice, Transgenic, Sex Factors, Aging physiology, Aging psychology, Alzheimer Disease physiopathology, Alzheimer Disease psychology, Anxiety physiopathology, Mesenteric Arteries physiopathology
- Abstract
Cardiovascular disease resulting from oxidative stress and inflammation can exacerbate Alzheimer's disease. This brief report provides the first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties in 15-month-old 3xTg-AD mice. Females showed worse physiologically relevant MRA structural (increased passive external and internal diameters, cross sectional area) and functional (increased active internal diameters) alterations suggesting sex-dependent dysfunctions. At both physiological and high intraluminal pressures, vascular alterations correlated with the anxious-like behavioral profile, in a sex-dependent manner. Finally, the results unveil a crosstalk between peripheral small vessel properties and behavior in both 3xTg-AD mice and age-matched counterparts with normal aging.
- Published
- 2018
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43. Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome.
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Jiménez-Altayó F, Siegert AM, Bonorino F, Meirelles T, Barberà L, Dantas AP, Vila E, and Egea G
- Abstract
Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 ( Fbn1 ) allele encoding a missense mutation ( Fbn1
C1039G/+ ), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications.- Published
- 2017
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44. Mediterranean tomato-based sofrito protects against vascular alterations in obese Zucker rats by preserving NO bioavailability.
- Author
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Rodriguez-Rodriguez R, Jiménez-Altayó F, Alsina L, Onetti Y, Rinaldi de Alvarenga JF, Claro C, Ogalla E, Casals N, and Lamuela-Raventos RM
- Subjects
- Animals, Biological Availability, Rats, Rats, Zucker, Vasoconstriction, Diet, Mediterranean, Solanum lycopersicum, Nitric Oxide metabolism, Obesity complications, Vascular Diseases prevention & control
- Abstract
Scope: Sofrito, a key component of the Mediterranean diet, provides nutritional interest due to its high content in bioactive compounds from tomato and olive oil, and especially to the lipid matrix in which these compounds are found. In this study, the potential beneficial effects of dietary intake of sofrito on obesity-related vascular alterations were explored in obese Zucker rats., Methods and Results: Obese and lean rats were fed a control diet supplemented or not with 2% w/w sofrito for 8 weeks. Vascular function was evaluated in aorta in organ baths. Dihydroethidium staining and immunofluorescence was used to determine aortic superoxide and peroxynitrite production, respectively. Despite food and caloric intake was higher in sofrito-fed obese rats, no differences were appreciated on body weight compared to control rats. Sofrito attenuated phenylephrine-induced vasoconstriction. This effect was associated with preservation of nitric oxide on vasoconstriction and normalization of serum nitric oxide metabolites, vascular inducible nitric oxide synthase and vascular superoxide and peroxynitrite levels., Conclusion: This is the first evidence of tomato-based sofrito protection against vascular alterations that could precede major cardiometabolic complications in obesity. These results contribute to explain the therapeutic properties of the Mediterranean diet in obesity-related disorders. Therefore, sofrito is an attractive dietary approach against vascular alterations in obesity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2017
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45. Activation of α 1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.
- Author
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Arce C, Vicente D, Segura V, Flacco N, Montó F, Almenar L, Agüero J, Rueda J, Jiménez-Altayó F, Vila E, Noguera MA, D'Ocon P, and Ivorra MD
- Subjects
- Animals, Aorta, Thoracic metabolism, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Rats, Rats, Inbred SHR, Rats, Wistar, Structure-Activity Relationship, Aging, Aorta, Thoracic drug effects, Nitric Oxide Synthase Type I metabolism, Phenylephrine pharmacology, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
Background and Purpose: A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of α
1 -adrenoceptors has been reported in different vessels. We investigated the involvement of each α1 -adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process., Experimental Approach: Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72 weeks-old, were used to evaluate the desensitization process. Expression of α1 -adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients with a wide age range., Key Results: Repeated application of phenylephrine decreased subsequent α1 -adrenoceptor-mediated vasoconstriction by increasing nNOS protein expression in aorta, but not in tail or mesenteric resistance arteries, where mRNA levels of nNOS were undetectable. This desensitization process disappeared in the absence of endothelium or in the presence of L-NAME (100 μM), nNOS inhibitors, SMTC (1 μM) and TRIM (100 μM), and 5-methylurapidil (100 nM, α1A -antagonist), but not BMY7378 (10 nM, α1D -antagonist). The α1A /nNOS-mediated desensitization was absent in aged SHR and Wistar animals, where the expression of α1A -adrenoceptors was reduced in aorta and LV. In human LV, a negative correlation was found between age and α1A -adrenoceptor expression., Conclusions and Implications: The α1A -adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological 'brake' against the detrimental effects of excessive α1 -adrenoceptor-mediated vasoconstriction. Reduced α1A -adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity., (© 2017 The British Pharmacological Society.)- Published
- 2017
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46. Treatment with Standard and Low Dose of Conjugated Equine Estrogen Differentially Modulates Estrogen Receptor Expression and Response to Angiotensin II in Mesenteric Venular Bed of Surgically Postmenopausal Hypertensive Rats.
- Author
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Araujo PX, Costa TJ, Echem C, Aparecida de Oliveira M, Santos-Eichler RA, Colli LG, Jiménez-Altayó F, Vila E, Akamine EH, Dantas AP, Ceravolo GS, and de Carvalho MHC
- Subjects
- Animals, Blood Pressure drug effects, Enzyme Inhibitors pharmacology, Female, Horses, Mice, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide biosynthesis, Nitric Oxide Synthase Type III antagonists & inhibitors, Ovariectomy, Rats, Inbred SHR, Receptor, Angiotensin, Type 2 drug effects, Angiotensin II pharmacology, Estrogens, Conjugated (USP) administration & dosage, Estrogens, Conjugated (USP) pharmacology, Postmenopause metabolism, Receptors, Estrogen biosynthesis, Splanchnic Circulation drug effects
- Abstract
Standard hormone therapy for menopausal women [conjugated equine estrogen (CEE) 0.625 mg] has been associated with increased risk of venous thrombosis. Regimens containing a lower CEE dose (0.30 mg) have been used clinically to decrease side effects of supraphysiologic doses of estrogen. In this study, we determined the effects of standard (SD) and low dose (LD) of CEE on venular function in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Contractions by angiotensin-II (Ang-II 10 μ M) in perfused mesenteric venular bed were markedly increased in OVX (21.5 ± 1.3 mmHg) compared with Sham (14.7 ± 1.1 mm Hg, P < 0.05). CEE-SD did not modify Ang-II responses in OVX, whereas CEE-LD restored Ang-II contraction to Sham levels. Endothelial nitric oxide synthase (eNOS) inhibition by L-NAME increased Ang-II contractions in Sham and CEE-LD and was without effect in venules of OVX SHR and CEE-SD. In OVX there was decreased NO generation in association with diminished eNOS phosphorylation and increased O
2 - generation in the venular wall. CEE-LD reverted the deleterious effects of ovariectomy. Although CEE-SD augmented eNOS phosphorylation in OVX, it was unable to increase NO levels, probably owing to its inability to reduce O2 - Distinct effects by CEE-SD and CEE-LD parallel the differential modulation of Ang-II and estrogen receptors. Compared with Sham, CEE-LD increases Ang II receptor type 2, whereas CEE-SD modified ER β expression in the venous bed. Interestingly, both CEE doses increased G protein-coupled estrogen receptor in OVX. Our data suggest that estrogen dose is an important factor for venous function. Although CEE-LD reversed deleterious effects of OVX, CEE-SD showed null effects despite its ability to increase eNOS activity., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2017
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47. Sphingosine-1-phosphate signalling-a key player in the pathogenesis of Angiotensin II-induced hypertension.
- Author
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Meissner A, Miro F, Jiménez-Altayó F, Jurado A, Vila E, and Planas AM
- Subjects
- Adoptive Transfer, Animals, Antihypertensive Agents pharmacology, Bone Marrow Transplantation, Cell Movement, Disease Models, Animal, Fingolimod Hydrochloride pharmacology, Genetic Predisposition to Disease, Hypertension chemically induced, Hypertension physiopathology, Hypertension prevention & control, Inflammation Mediators metabolism, Lymph Nodes drug effects, Mesenteric Arteries metabolism, Mesenteric Arteries physiopathology, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Phosphotransferases (Alcohol Group Acceptor) deficiency, Phosphotransferases (Alcohol Group Acceptor) genetics, Receptors, Lysosphingolipid antagonists & inhibitors, Receptors, Lysosphingolipid metabolism, Signal Transduction, Sphingosine blood, T-Lymphocytes drug effects, T-Lymphocytes transplantation, Time Factors, Vascular Remodeling, Angiotensin II, Blood Pressure drug effects, Hypertension metabolism, Lymph Nodes metabolism, Lysophospholipids blood, Sphingosine analogs & derivatives, T-Lymphocytes metabolism
- Abstract
Aims: Hypertension is a complex condition involving functional and structural alterations of the microvasculature and an activation of the immune system. T-lymphocytes play a crucial role during the development of hypertension in experimental models, yet the underlying mechanisms remain elusive. Lymphocyte egress from lymph nodes is controlled by sphingosine-1-phosphate (S1P), a natural lipid mediator regulating immune cell and vascular function in health and disease. We therefore investigated the involvement of S1P signalling in the pathogenesis of hypertension., Methods and Results: Angiotensin-II (AngII) treatment resulted in high blood pressure (BP) associated to increased plasma S1P and circulating T-cell counts. T-cell egress from lymph nodes was found to be a critical initial step for the onset of hypertension as fingolimod, a S1P-receptor agonist sequestering lymphocytes in the lymph nodes and inducing lymphopenia, blunted BP responses to AngII. Furthermore, activity of S1P-generating enzyme type 2 (SphK2) in haematopoietic cells critically contributed to AngII-induced lymphocyte mobilization from the lymph nodes as SphK2
-/- mice and mice where SphK2 was ablated only in the haematopoietic system presented an accumulation of T-cells in mesenteric lymph nodes and a blunted BP response. In addition, deregulation of vascular SphK2 expression associated to a thrombo-inflammatory phenotype of the microvasculature, and to functional alterations of small resistance arteries., Conclusion: The presented results point to a critical involvement of S1P and its signalling axis in the pathogenesis of hypertension. Specifically, SphK2 evolves as key player in immune cell trafficking and vascular dysfunction contributing to the development of overt hypertension., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)- Published
- 2017
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48. Sex differences in angiotensin II responses contribute to a differential regulation of cox-mediated vascular dysfunction during aging.
- Author
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Costa G, Garabito M, Jiménez-Altayó F, Onetti Y, Sabate M, Vila E, and Dantas AP
- Subjects
- Animals, Cyclooxygenase 2 metabolism, Endothelium, Vascular drug effects, Female, Indomethacin pharmacology, Losartan pharmacology, Male, Mice, Oxidative Stress drug effects, Vasodilation drug effects, Aging physiology, Angiotensin II metabolism, Angiotensin II Type 1 Receptor Blockers pharmacology, Prostaglandins metabolism, Renin-Angiotensin System drug effects, Sex Factors
- Abstract
Aging is a cardiovascular risk factor partially related to activation of the Renin-Angiotensin System (RAS). RAS activation is also influenced by sex. In this regard, our study aims to determine whether sex-associated differences in RAS contribute to a differential regulation of vascular aging and associated dysfunction. Male and female outbreed CD-1 mice were studied at 3 and 12months of age (M). Contribution of RAS was determined by treating mice from 3M to 12M with the AngII type 1 receptor blocker losartan (0.6g/L in the drinking water). At 12M, contractions to AngII were higher in males compared to females (P<0.05). This effect was paralleled by a decrease in AngII type 2 receptors in 12M males. Aging also diminished ACh relaxation in males, but did not modify female responses. Treatment of aortas with indomethacin (10μM) restored the impaired endothelium-dependent relaxation in 12M males, suggesting an increase of cyclooxygenase (COX)-derived vasoconstrictors in aged males. Chronic treatment of mice with losartan also improved endothelium-dependent relaxation. Besides, losartan significantly decreased COX-2 expression and activity in 12M male, with a minor effect in aged females. Aging increases AngII contraction and induces endothelial dysfunction differently in males and females. In aged males, RAS contributed to increased COX-2 expression and activity, which in turn may lead to vascular dysfunction., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
49. NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome.
- Author
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Onetti Y, Meirelles T, Dantas AP, Schröder K, Vila E, Egea G, and Jiménez-Altayó F
- Subjects
- Animals, Arterial Pressure, Cerebrovascular Disorders enzymology, Cerebrovascular Disorders genetics, Cerebrovascular Disorders pathology, Collagen metabolism, Disease Models, Animal, Disease Progression, Female, Fibrillin-1 genetics, Genetic Predisposition to Disease, Male, Marfan Syndrome enzymology, Marfan Syndrome genetics, Mechanotransduction, Cellular, Mice, Knockout, Middle Cerebral Artery pathology, Middle Cerebral Artery physiopathology, NADH, NADPH Oxidoreductases metabolism, NADPH Oxidase 1, NADPH Oxidase 4, NADPH Oxidases deficiency, NADPH Oxidases genetics, Phenotype, Reactive Oxygen Species metabolism, Stress, Mechanical, Time Factors, Transforming Growth Factor beta metabolism, Vascular Stiffness, Cerebrovascular Disorders prevention & control, Marfan Syndrome complications, Middle Cerebral Artery enzymology, NADPH Oxidases metabolism, Vascular Remodeling
- Abstract
Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm(2); Marfan Nox4(-/-): 8,795 ± 824 μm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
50. Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: a target of uric acid treatment.
- Author
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Onetti Y, Dantas AP, Pérez B, Cugota R, Chamorro A, Planas AM, Vila E, and Jiménez-Altayó F
- Subjects
- Animals, Hyperemia drug therapy, Infarction, Middle Cerebral Artery drug therapy, Infarction, Middle Cerebral Artery metabolism, Interleukin-18 genetics, Interleukin-18 metabolism, Male, Oxidative Stress, Rats, Rats, Sprague-Dawley, Antioxidants therapeutic use, Hyperemia physiopathology, Infarction, Middle Cerebral Artery physiopathology, Uric Acid therapeutic use
- Abstract
Ischemia impairs blood supply to the brain, and reperfusion is important to restore cerebral blood flow (CBF) and rescue neurons from cell death. However, reperfusion can induce CBF values exceeding the basal values before ischemia. This hyperemic effect has been associated with a worse ischemic brain damage, albeit the mechanisms that contribute to infarct expansion are not clear. In this study, we investigated the influence of early postischemic hyperemia on brain damage and middle cerebral artery (MCA) properties and the effect of treatment with the endogenous antioxidant uric acid (UA). The MCA was occluded for 90 min followed by 24 h reperfusion in adult male Sprague-Dawley rats. Cortical CBF increases at reperfusion beyond 20% of basal values were taken as indicative of hyperemia. UA (16 mg/kg) or vehicle (Locke's buffer) was administered intravenously 135 min after MCA occlusion. Hyperemic compared with nonhyperemic rats showed MCA wall thickening (sham: 22.4 ± 0.8 μm; nonhyperemic: 23.1 ± 1.2 μm; hyperemic: 27.8 ± 0.9 at 60 mmHg; P < 0.001, hyperemic vs. sham) involving adventitial cell proliferation, increased oxidative stress, and interleukin-18, and more severe brain damage. Thus MCA remodeling after ischemia-reperfusion takes place under vascular oxidative and inflammatory stress conditions linked to hyperemia. UA administration attenuated MCA wall thickening, induced passive lumen expansion, and reduced brain damage in hyperemic rats, although it did not increase brain UA concentration. We conclude that hyperemia at reperfusion following brain ischemia induces vascular damage that can be attenuated by administration of the endogenous antioxidant UA., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
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