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Individuals with metabolic syndrome (MetS) are prone to develop heart failure (HF). However, the deleterious effects of MetS on the continuum of events leading to cardiac remodeling and subsequently to HF are not fully understood. This study characterized simultaneously MetS and cardiac, vascular and renal phenotypes in aging Spontaneously Hypertensive Heart Failure lean (SHHF+/? regrouping +/+ and +/cp rats) and obese (SHHFcp/cp, “cp” defective mutant allele of the leptin receptor gene) rats. We aimed to refine the milestones and their onset during the progression from MetS to HF in this experimental model. We found that SHHFcp/cp but not SHHF+/? rats developed dyslipidemia, as early as 1.5 months of age. This early alteration in the lipidic profile was detectable concomitantly to impaired renal function (polyuria, proteinuria but no glycosuria) and reduced carotid distensibility as compared to SHHF+/? rats. By 3 months of age SHHFcp/cp animals developed severe obesity associated with dislipidemia and hypertension defining the onset of MetS. From 6 months of age, SHHF+/? rats developed concentric left ventricular hypertrophy (LVH) while SHHFcp/cp rats developed eccentric LVH apparent from progressive dilation of the LV dimensions. By 14 months of age only SHHFcp/cp rats showed significantly higher central systolic blood pressure and a reduced ejection fraction resulting in systolic dysfunction as compared to SHHF+/?. In summary, the metabolic and hemodynamic mechanisms participating in the faster decline of cardiac functions in SHHFcp/cp rats are established long before their physiological consequences are detectable. Our results suggest that the molecular mechanisms triggered within the first three months after birth of SHHFcp/cp rats should be targeted preferentially by therapeutic interventions in order to mitigate the later HF development. [ABSTRACT FROM AUTHOR]

BACKGROUND We examined the influence of the AGTR1 A1166C genotype on the 16-year evolution of pulse wave velocity (PWV) in a middle-aged population. In a cross-sectional study, we reported that the presence of the AGTR1 1166C allele was associated with higher aortic stiffness compared with the AGTR1 1166AA genotype. METHODS The study was conducted in 259 subjects who underwent 3 health check-ups over 16 years at the Centre IPC–Paris: an initial visit in 1992–1993, an intermediate visit in 1998–1999, and a final visit in 2007–2008. Aortic stiffness was assessed during the 3 visits by measuring carotid–femoral PWV. AGTR1 A1166C polymorphism was assayed by allele-specific oligonucleotide hybridization. RESULTS AGTR1 1166C allele carriers (AC + CC genotypes) had a 35% more pronounced increase in PWV over this 16-year period when compared with the AGTR1 1166AA subjects (3.01±0.32 vs. 1.92±0.23 m/s; P < 0.001). This increase remained significant after adjustment for age, sex, initial PWV values, and changes in blood pressure (+37%; P < 0.05). The genotype-related differences in PWV were only observed at the last visit (i.e., later in life, after the age of 55 years). The effects of this genotype on PWV were not related to the presence of antihypertensive treatment. CONCLUSIONS This is the first long-term longitudinal study indicating that AT1 1166C carriers are at increased risk of pronounced arterial stiffening during aging especially after the age of 55. [ABSTRACT FROM PUBLISHER]

The vast majority of glomerular filtrated phosphate is reabsorbed in the proximal tubule. Posttransplant phosphaturia is common and aggravated by sirolimus immunosuppression. The cause of sirolimus induced phosphaturia however remains elusive. Male Wistar rats received sirolimus or vehicle for 2 or 7 days (1.5mg/kg). The urine phosphate/creatinine ratio was higher and serum phosphate was lower in sirolimus treated rats, fractional excretion of phosphate was elevated and renal tubular phosphate reabsorption was reduced suggesting a renal cause for hypophosphatemia. PTH was lower in sirolimus treated rats. FGF 23 levels were unchanged at day 2 but lower in sirolimus treated rats after 7 days. Brush border membrane vesicle phosphate uptake was not altered in sirolimus treated groups or by direct incubation with sirolimus. mRNA, protein abundance, and subcellular transporter distribution of NaPi-IIa, Pit-2 and NHE3 were not different between groups but NaPi- IIc mRNA expression was lower at day 7. Transcriptome analyses revealed candidate genes that could be involved in the phosphaturic response. Sirolimus caused a selective renal phosphate leakage, which was not mediated by NaPi-IIa or NaPi- IIc regulation or localization. We hypothesize that another mechanism such as a basolateral phosphate transporter may be responsible for the sirolimus induced phosphaturia. [ABSTRACT FROM AUTHOR]

Pathophysiological aldosterone (aldo)/ mineralocorticoid receptor (MR) signaling has significant effects on the cardiovascular system, resulting in hypertension and cardiovascular remodeling; however, the specific contribution of the vascular MR to blood pressure regulation remains to be established. To address this question, we generated a mouse model with conditional overexpression of the MR in endothelial cells (MR-EC). In basal conditions, MR-EC mice developed moderate hypertension that could be reversed by canrenoate, a pharmacological MR antagonist. MR-EC mice presented increased contractile response of resistance arteries to vasoconstrictors (phenylephrine, thromboxane A2 analog, angiotensin II, and endothelin 1) in the absence of vascular morphological alterations. The acute blood pressure response to angiotensin II or endothelin 1 infusion was increased in MR-EC mice compared with that in littermate controls. These observations demonstrate that enhanced MR activation in the endothelium generates an increase in blood pressure, independent of stimulation of renal tubular Na+ transport by aldo/MR or direct activation of smooth muscle MR and establish one mechanism by which endothelial MR activation per se may contribute to impaired vascular reactivity. [ABSTRACT FROM AUTHOR]

BackgroundThe Saharan adult population is characterized by a high prevalence of hypertension. The aim of the present study was to compare blood pressure (BP) levels in Saharan Arab-origin teenagers, in relationship with Europeans of the same age, and to assess the association with birth weight, body weight, and other anthropometric measurements.MethodsBP values, heart rate (HR), clinical parameters, and anthropometric measurements were determined in 2,057 teenagers ages 15–19, 1,122 Algerians (388 boys) and 935 Italians (407 boys). Birth weight was obtained from obstetrical records in 568 Algerians and 735 Italians.ResultsThe European teenagers were significantly taller and heavier than their Algerian counterparts. In the Algerian population, systolic BP (SBP) was higher in boys (P < 0.01) and lower in girls (P < 0.0001) compared to the Italians, whereas diastolic BP (DBP) was higher in Italians (P < 0.001). Both SBP and DBP were higher in boys than in girls independently of geographic origin (P < 0.001). In all four gender and ethnic groups, both SBP and DBP were strongly correlated with weight or body mass index (BMI). Influence of body weight was stronger on SBP than on DBP; in all four groups, those with the highest weight or BMI quartiles had higher SBP levels by 6–12 mm Hg as compared to those individuals in the lowest quartiles. No correlation was found between birth weight, and SBP or DBP.ConclusionsIn Algerian and Italian teenagers, both male and female, current weight but not birth weight was found to be a strong determinant of BP levels.American Journal of Hypertension 2010; doi:10.1038/ajh.2009.275 [ABSTRACT FROM AUTHOR]

BackgroundMeta-analyses of antihypertensive therapy suggest that, independently of blood pressure (BP) level, stroke prevention is influenced mainly by calcium-entry blockers (CEB) and cardiac risk prevention by angiotensin-converting enzyme inhibitors (ACEIs). The possibility that central systolic and pulse pressure (PP) reduction differs between the two drug classes for the same mean BP (MBP) has never been explored. Our aim was to compare carotid PP at the same MBP obtained with the CEB, amlodipine, and the ACEI, trandolapril, in spontaneously hypertensive rats (SHR), and to evaluate the resulting changes of fibronectin (Fn) and its integrin α5β1 receptor on central PP and arterial stiffness.MethodsAmlodipine and trandolapril were administered chronically to achieve the same MBP. Carotid arterial systolic BP (SBP) and PP, diameter and incremental elastic modulus (Einc) were determined using echo Doppler techniques, and complemented with vascular histomorphometry, and Fn and α5β1-integrin immunolabeling.ResultsBoth drugs produced the same MBP, carotid wall thickness, and stress. Trandolapril reduced PP and Einc significantly more than amlodipine, while both agents comparably lowered EIIIA-Fn. Total Fn and α-subunit were lowered significantly by trandolapril, but unaffected by amlodipine, indicating that ACEI alone contributed to both diminished carotid stiffness and decrease of the Fn–integrin complex.ConclusionsResults showed that amlodipine and trandolapril have different effects on carotid mechanical properties for comparable MBP reduction. Changes in Fn–integrin complex not only modify consistently ACEI mechanotransduction but also are associated with selective central PP reduction. Whether this property has consequences on cardiovascular (CV) risk remains to be investigated.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.87American Journal of Hypertension 2009; 22, 7, 711–717. doi:10.1038/ajh.2009.87 [ABSTRACT FROM AUTHOR]

We examined the arterial phenotype of mice lacking α1-integrin (α1-/-) at baseline and after 4 wk of ANG II or norepinephrine (NE) administration. Arterial mechanical properties were determined in the carotid artery (CA). Integrin expression, MAPK kinases, and focal adhesion kinase (FAK) were assessed in the aorta. No change in arterial pressure was observed in α1-/- mice. Elastic modulus-wall stress curves were similar in α1-/- and α1-/- animals, indicating no change in arterial stiffness. The rupture pressure was lower in α1-/- mice, demonstrating decreased mechanical strength. Lack of α1-integrin was accompanied by an increase in β1-, αv-, and α5-integrins but no change in α2-integrin. ANG II increased medial cross-sectional area of the CA in α1+/+, but not α1-/-, mice, whereas equivalent pressor doses of NE did not produce a significant increase in either group. In α1+/+ mice, ANG II induced α1-integrin expression and smooth muscle cell (SMC) hypertrophy in the CA in association with increased aortic expression of α-smooth muscle actin and smooth muscle myosin heavy chain and phosphorylation of ERK 1/2, p38 MAPK, and FAK. ANG II did not induce SMC hypertrophy or phosphorylation of p38 MAPK and FAK in α1-/- mice. A functional anti-α1-integrin antibody inhibited in vitro the ANG II-induced phosphorylation of FAK and p38 MAPK. In conclusion, α1-/- mice exhibit a reduced mechanical strength at baseline and a lack of ANG II-induced SMC hypertrophy. These results emphasize the importance of α1β1-integrin in p38 MAPK and FAK phosphorylation during vascular hypertrophy in response to ANG II. [ABSTRACT FROM AUTHOR]

Background: We examined the effects of early high salt diet (HSD) and angiotensin II type 1 (AT1) receptor antagonist valsartan (Val) on mortality and carotid distensibility in surviving spontaneously hypertensive rats (SHRs). Methods: The HSD was initiated either early (week 4 after birth) or late (week 10), continued until 20 weeks of age, and compared to normal salt diet (NSD) groups. Valsartan was given from the fourth week after birth. Results: Eighty-six percent of the rats died in early HSD on placebo, 70% in early HSD on Val-3 mg, 35% in early HSD on Val-30 mg, and 13% in late HSD on placebo. Mean arterial pressure (MAP) was higher in the early HSD and late HSD groups on placebo compared with NSD. The Val-30 mg reduced MAP in all except early HSD groups. Distensibility at MAP (operational distensibility) was lower in late HSD on placebo than in NSD placebo groups. The Val-30 mg increased distensibility in NSD groups. There was no effect of Val in late HSD and early HSD groups. Operational distensibility was negatively correlated with MAP and salt and positively correlated with Val treatment. All animals receiving HSD showed a higher isobaric distensibility in early HSD than in late HSD groups and a smaller distensibility in rats treated with Val. Conclusions: Our results showed that administration of early HSD in SHR was associated together with a high mortality, a protective action of Val that increased longevity, and an increased level of isobaric distensibility. Survival in HSD groups suggest a direct role of angiotensin II in salt-induced cardiovascular mortality. This role is associated with MAP independent of changes in carotid stiffness. [Copyright &y& Elsevier]

Abstract: Objective: We examined the arterial phenotype of semicarbazide-sensitive amine-oxidase null mouse (SSAO −/−) using various techniques including high resolution echotracking. Methods and results: SSAO −/− mice showed no change in arterial pressure under anesthesia. The in vivo arterial diameter, only measured in the carotid artery (CA), was higher in SSAO −/− than in SSAO +/+ animals. Elastic modulus–wall stress curves and CA rupture pressure were similar between SSAO −/− and +/+ mice, indicating no change in arterial wall stiffness or mechanical strength. There was no significant difference in insoluble elastin, total collagen content and elastic lamellar morphology between the two genotypes. No alteration in vascular reactivity was observed in aortic rings and mesenteric arteries from SSAO −/− mice. Aortic lysyl oxidase (LO) activity remained unaltered, indicating that SSAO invalidation is not accompanied by a compensatory increase in LO activity. Conclusion: This is the first functional study of arteries lacking SSAO. Our results indicate that SSAO −/− mice present an increased arterial diameter associated with normal arterial mechanical properties, suggesting that SSAO deficiency might contribute to arterial wall remodeling. However, these results argue against the hypothesis that SSAO intervenes in elastic fibre organization, elastin cross-linking processes and vasoreactivity. [Copyright &y& Elsevier]

Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context. [ABSTRACT FROM AUTHOR]