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Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. Acute administration of losartan significantly reduced participants' adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development. [ABSTRACT FROM AUTHOR]

Hyperthyroidism is a condition where the thyroid gland produces high levels of thyroid hormone. Heart diseases are one of the main complications of hyperthyroidism. Several studies have shown that losartan (LOS) and diminazene aceturate (DIZE) possess cardioprotection effects against cardiac hypertrophy, ischemic heart disease, and heart failure. The research aimed to investigate the cardioprotection of LOS, DIZE, and their combination in the case of levothyroxine (LT4)-induced cardiomyopathy in rats. Hyperthyroidism was induced by LT4 in drinking water (12 mg/L) for 28 days. LOS (10 mg/kg, orally) and/or DIZE (15 mg/kg, subcutaneously) were administrated in rats with hyperthyroidism for 28 days. Decreased serum creatine kinase myoglobin and lactate dehydrogenase levels and cardiac hypertrophy by DIZE and combination therapy in hyperthyroidism rats have been reported. Cardiac hemodynamic findings showed that DIZE and its combination with LOS decreased the LT4-mediated left ventricular developed pressure (LVDP), rate pressure product (RPP), and RPP recovery percentage. Elevated cardiac oxidative stress and inflammation were confirmed by decreasing cardiac superoxide dismutase (SOD) activity and increasing the total oxidative stress and tumor necrosis factor-alpha (TNF-α) levels. SOD activity and TNF-α level were reversed by LOS and DIZE administration, respectively. Generally, DIZE and combination therapy with LOS improved cardiac dysfunction caused by hyperthyroidism in rats, whereas LOS alone has not been able to effectively respond to this dysfunction. [ABSTRACT FROM AUTHOR]

β-arrestins are a family of intracellular signaling proteins that play a key role in regulating the activity of G proteincoupled receptors. The angiotensin-II type 1 receptor is an important G protein-coupled receptor involved in the regulation of cardiovascular function and has been implicated in the progression of cardiovascular diseases. In addition to canonical G protein signaling, G protein-coupled receptors including the angiotensin-II type 1 receptor can signal via β-arrestin. Dysregulation of β-arrestin signaling has been linked to several cardiovascular diseases including hypertension, atherosclerosis, and heart failure. Understanding the role of β-arrestins in these conditions is critical to provide new therapeutic targets for the treatment of cardiovascular disease. In this review, we will discuss the beneficial and maladaptive physiological outcomes of angiotensin-II type 1 receptor-dependent β-arrestin activation in different cardiovascular diseases. [ABSTRACT FROM AUTHOR]

La infección por el nuevo SARS-CoV 2 se ha convertido en el mayor problema de salud pública mundial desde la aparición de la enfermedad en 2019 en China; A partir de ese momento, la comunidad médica y científica se ha enfocado en describir los mecanismos fisiopatológicos de la infección para ofrecer mejores alternativas de tratamiento a los pacientes y hacer pronósticos de la infección, sin embargo, se deben considerar las regiones anatómicas donde infecta el virus. El objetivo de esta revisión es describir los sitios de colonización del virus, los mecanismos subyacentes de lesión en órganos y sistemas, y las consecuencias provocadas por la infección. Para esta investigación se realizó una búsqueda de la literatura más reciente sobre el COVID-19 y su asociación con el receptor ACE-2.

[Figure: see text].

Objective(s): Chronic kidney disease (CKD), accompanied by renal dysfunction, fibrosis, and apoptosis, is highly prevalent in postmenopausal women. We tested the hypothesis that isoflavone daidzein may ameliorate renal dysfunction and fibrosis through angiotensin II type 1 (AT1R) and angiotensin 1-7 (MasR) receptors in association with microRNAs 33a and 27a.Materials and Methods: Two weeks before the initiation of the experiments, rats (n=84) underwent ovariectomy (OVX). Then, unilateral ureteral obstruction (UUO) was performed in OVX rats, and animals were allocated to the following groups (n=21): sham vehicle (dimethyl sulfoxide; DMSO 1%), UUO vehicle, UUO+17β-estradiol (E2), and UUO+daidzein. Each group encompassed three subgroups (n=7) treated with saline, A779 (MasR antagonist), or losartan (AT1R antagonist) for 15 days. The fractional urine excretion of sodium (FENa+) and potassium (FEK+), renal failure index (RFI), renal interstitial fibrosis (RIF index), glomerulosclerosis, miR-33a, and miR-27a expressions and their target genes were analyzed. Apoptosis was measured via cleaved caspase-3 immunohistochemistry.Results: UUO increased kidney weight, FENa+, FEK+, urine calcium, RFI, RIF index, glomerulosclerosis, and cleaved caspase-3. Moreover, expression of renal miR-33a and miR-27a, collagen3A1 mRNA, and protein were up-regulated post-UUO. Daidzein treatment alleviated the harmful effects of UUO especially in co-treatment with losartan. They also masked the anticipated worsening effects of A779 on UUO.Conclusion: Compared with E2, daidzein efficiently ameliorated renal dysfunction, fibrosis, and apoptosis through modulation of miR-33a and miR-27a expression and their crosstalk with AT1R and MasR. Therefore, daidzein might be a promising candidate for treating CKD in postmenopausal and older women.

Objective(s): Chronic kidney disease (CKD), accompanied by renal dysfunction, fibrosis, and apoptosis, is highly prevalent in postmenopausal women. We tested the hypothesis that isoflavone daidzein may ameliorate renal dysfunction and fibrosis through angiotensin II type 1 (AT1R) and angiotensin 1-7 (MasR) receptors in association with microRNAs 33a and 27a. Materials and Methods: Two weeks before the initiation of the experiments, rats (n=84) underwent ovariectomy (OVX). Then, unilateral ureteral obstruction (UUO) was performed in OVX rats, and animals were allocated to the following groups (n=21): sham vehicle (dimethyl sulfoxide; DMSO 1%), UUO vehicle, UUO+17β-estradiol (E2), and UUO+daidzein. Each group encompassed three subgroups (n=7) treated with saline, A779 (MasR antagonist), or losartan (AT1R antagonist) for 15 days. The fractional urine excretion of sodium (FENa+) and potassium (FEK+), renal failure index (RFI), renal interstitial fibrosis (RIF index), glomerulosclerosis, miR-33a, and miR-27a expressions and their target genes were analyzed. Apoptosis was measured via cleaved caspase-3 immunohistochemistry. Results: UUO increased kidney weight, FENa+, FEK+, urine calcium, RFI, RIF index, glomerulosclerosis, and cleaved caspase-3. Moreover, expression of renal miR-33a and miR-27a, collagen3A1 mRNA, and protein were up-regulated post-UUO. Daidzein treatment alleviated the harmful effects of UUO especially in co-treatment with losartan. They also masked the anticipated worsening effects of A779 on UUO. Conclusion: Compared with E2, daidzein efficiently ameliorated renal dysfunction, fibrosis, and apoptosis through modulation of miR-33a and miR-27a expression and their crosstalk with AT1R and MasR. Therefore, daidzein might be a promising candidate for treating CKD in postmenopausal and older women. [ABSTRACT FROM AUTHOR]

Recent studies have shown that fascial fibroblasts are sensitive to different stimuli (biochemical or biophysical), promoting extracellular matrix remodeling, as well as synthetic activity. Moreover, the extensive literature on the renin–angiotensin system (RAS) reported its involvement in tissue remodeling. This study aimed to investigate the presence of RAS components in the deep fascia. Thoracolumbar fascia specimens were collected from 13 patients (age range: 25–75 years; seven males and five females) who had undergone elective spinal surgical procedures at the Orthopedic Clinic of the University of Padova. Gene expression analysis was performed to investigate the expression of Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), MAS receptor (MasR), angiotensinogen, angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme 1 (ACE1). AT1R and ACE2 were also measured with immunoblot. AT1R was the most expressed angiotensin receptor subtype (300.2 ± 317 copies/25 ng of mRNA), followed by MasR (37.1 ± 39.56 copies/25 ng of mRNA) and AT2R (147 ± 122 copies/25 ng of mRNA). The amounts of angiotensinogen, ACE1 and ACE2 were hardly detectable. These findings demonstrate that RAS system receptors are present in the deep fascia, with a greater expression of AT1R, suggesting their involvement in fascial remodeling and fibrogenesis. [ABSTRACT FROM AUTHOR]

This study investigated the impacts of enteral cholecalciferol and/or intravenous calcitriol administration on the balance of cluster of differentiation 4-positive T cell subsets, the renin-angiotensin system (RAS), and the severity of acute lung injury (ALI) in obese mice with sepsis. Mice were fed a high-fat diet and then cecal ligation and puncture (CLP) was performed. Obese mice were divided into four sepsis groups: without vitamin D (VD) (S), with oral cholecalciferol 1 d before CLP (G), with intravenous calcitriol 1 h after CLP (V), and with both cholecalciferol before and intravenous calcitriol after CLP (GV). Mice were euthanized after CLP. The V and GV groups showed higher blood T helper (Th)1/Th2 and lower Th17/T regulatory (Treg) ratios than did the S and G groups. In the lungs, The V group had the lowest nuclear factor-κB and interleukin-1β gene expressions among all groups 24 h post-CLP. In parallel, gene expressions of angiotensin type 2 receptor (AT2R), angiotensin-converting enzyme 2 (ACE2), and Mas receptor (MasR) were highest in the V group compared to other groups. The protein levels of MasR in the GV group and the AT2R/AT1R ratio in the V group were higher than those in the G and/or S groups. All of the VD-treated groups had lower injury scores than the S group. These findings suggest that calcitriol administration had more-pronounced impacts on regulating the homeostasis of Th/Treg cells and is prone to RAS-associated anti-inflammatory pathway in the lungs. However, both forms of VD attenuated sepsis-induced ALI in obese animals.

The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review the etiology of inverse salt sensitivity of blood pressure (BP). Recent Findings: Both high and low sodium (Na+) intake can be associated with increased BP and cardiovascular morbidity and mortality. However, little is known regarding the mechanisms involved in the increase in BP in response to low Na+ intake, a condition termed inverse salt sensitivity of BP, which affects approximately 15% of the adult population. The renal proximal tubule is important in regulating up to 70% of renal Na+ transport. The renin-angiotensin and renal dopaminergic systems play both synergistic and opposing roles in the regulation of Na+ transport in this nephron segment. Clinical studies have demonstrated that individuals express a "personal salt index" (PSI) that marks whether they are salt-resistant, salt-sensitive, or inverse salt-sensitive. Inverse salt sensitivity results in part from genetic polymorphisms in various Na+ regulatory genes leading to a decrease in natriuretic activity and an increase in renal tubular Na+ reabsorption leading to an increase in BP. Summary: This article reviews the potential mechanisms of a new pathophysiologic entity, inverse salt sensitivity of BP, which affects approximately 15% of the general adult population. [ABSTRACT FROM AUTHOR]

Abstract Background Treatment of heart failure with reduced ejection fraction (HFrEF) has been revolutionized by angiotensin receptor/neprilysin inhibitor (ARNI). ARNI has been shown to significantly reduce morbidity and mortality in a large, randomized controlled trial. However, real-world evaluation of ARNI with a diverse population is still limited. Methods HFrEF patients receiving angiotensin receptor/neprilysin inhibitor (ARNI) or standard HF treatment at a university hospital in Thailand were prospectively followed-up from January 2015 to December 2019. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Survival analysis and the Cox proportional hazard model were used to compare clinical outcomes between the two groups. Results During a follow-up period of 12 months, the primary outcome occurred in 10 patients in the ARNI group (11.5%) and 28 in the standard treatment group (28.0%) (hazard ratio 0.34; 95% CI: 0.15–0.80; p = 0.013). After adjustment for confounding factors, ARNI was significantly associated with a significant reduction in the primary outcome (HR 0.32, 95% CI: 0.13–0.82, p = 0.017). In addition, ARNI was also significantly associated with a decrease in the clinical signs and symptoms of HF, including dyspnea, orthopnea, and fatigue. Orthostatic hypotension was more frequently reported among the ARNI group than among the standard treatment group. The rates of target dose achievement were comparable between the two groups. Conclusion In real-world practice, ARNI use was associated with a significant reduction in both clinical outcomes and symptom improvement, while orthostatic hypotension was more common in patients in the ARNI group than in patients in the standard treatment group.

The angiotensin type 2 (AT2) receptor and the bradykinin type 2 (B2) receptor are G protein-coupled receptors (GPCRs) that have major roles in the cardiovascular system. The two receptors are known to functionally interact at various levels, and there is some evidence that the observed crosstalk may occur as a result of heteromerization. We investigated evidence for heteromerization of the AT2 receptor and the B2 receptor in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)- proximity based assays, including the Receptor Heteromer Investigation Technology (Receptor-HIT) and the NanoBRET ligand-binding assay. The Receptor-HIT assay showed that Gaq, GRK2 and b-arrestin2 recruitment proximal to AT2 receptors only occurred upon B2 receptor coexpression and activation, all of which is indicative of AT2-B2 receptor heteromerization. Additionally, we also observed specific coupling of the B2 receptor with the Gaz protein, and this was found only in cells coexpressing both receptors and stimulated with bradykinin. The recruitment of Gaz, Gaq, GRK2 and barrestin2 was inhibited by B2 receptor but not AT2 receptor antagonism, indicating the importance of B2 receptor activation within AT2-B2 heteromers. The close proximity between the AT2 receptor and B2 receptor at the cell surface was also demonstrated with the NanoBRET ligand-binding assay. Together, our data demonstrate functional interaction between the AT2 receptor and B2 receptor in HEK293FT cells, resulting in novel pharmacology for both receptors with regard to Gaq/GRK2/b-arrestin2 recruitment (AT2 receptor) and Gaz protein coupling (B2 receptor). Our study has revealed a new mechanism for the enigmatic and poorly characterized AT2 receptor to be functionally active within cells, further illustrating the role of heteromerization in the diversity of GPCR pharmacology and signaling. [ABSTRACT FROM AUTHOR]

The angiotensin type 2 (AT2) receptor and the bradykinin type 2 (B2) receptor are G protein-coupled receptors (GPCRs) that have major roles in the cardiovascular system. The two receptors are known to functionally interact at various levels, and there is some evidence that the observed crosstalk may occur as a result of heteromerization. We investigated evidence for heteromerization of the AT2 receptor and the B2 receptor in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)-proximity based assays, including the Receptor Heteromer Investigation Technology (Receptor-HIT) and the NanoBRET ligand-binding assay. The Receptor-HIT assay showed that Gαq, GRK2 and β-arrestin2 recruitment proximal to AT2 receptors only occurred upon B2 receptor coexpression and activation, all of which is indicative of AT2-B2 receptor heteromerization. Additionally, we also observed specific coupling of the B2 receptor with the Gαz protein, and this was found only in cells coexpressing both receptors and stimulated with bradykinin. The recruitment of Gαz, Gαq, GRK2 and β-arrestin2 was inhibited by B2 receptor but not AT2 receptor antagonism, indicating the importance of B2 receptor activation within AT2-B2 heteromers. The close proximity between the AT2 receptor and B2 receptor at the cell surface was also demonstrated with the NanoBRET ligand-binding assay. Together, our data demonstrate functional interaction between the AT2 receptor and B2 receptor in HEK293FT cells, resulting in novel pharmacology for both receptors with regard to Gαq/GRK2/β-arrestin2 recruitment (AT2 receptor) and Gαz protein coupling (B2 receptor). Our study has revealed a new mechanism for the enigmatic and poorly characterized AT2 receptor to be functionally active within cells, further illustrating the role of heteromerization in the diversity of GPCR pharmacology and signaling.

Recent studies have shown that fascial fibroblasts are sensitive to different stimuli (biochemical or biophysical), promoting extracellular matrix remodeling, as well as synthetic activity. Moreover, the extensive literature on the renin–angiotensin system (RAS) reported its involvement in tissue remodeling. This study aimed to investigate the presence of RAS components in the deep fascia. Thoracolumbar fascia specimens were collected from 13 patients (age range: 25–75 years; seven males and five females) who had undergone elective spinal surgical procedures at the Orthopedic Clinic of the University of Padova. Gene expression analysis was performed to investigate the expression of Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), MAS receptor (MasR), angiotensinogen, angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme 1 (ACE1). AT1R and ACE2 were also measured with immunoblot. AT1R was the most expressed angiotensin receptor subtype (300.2 ± 317 copies/25 ng of mRNA), followed by MasR (37.1 ± 39.56 copies/25 ng of mRNA) and AT2R (147 ± 122 copies/25 ng of mRNA). The amounts of angiotensinogen, ACE1 and ACE2 were hardly detectable. These findings demonstrate that RAS system receptors are present in the deep fascia, with a greater expression of AT1R, suggesting their involvement in fascial remodeling and fibrogenesis.

[Figure: see text]. [ABSTRACT FROM AUTHOR]

The renal nephron consists of a series of distinct cell types that function in concert to maintain fluid and electrolyte balance and blood pressure. The renin-angiotensin system (RAS) is central to Na+ and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered Na+ and volume, impacts solute transport throughout the nephron. We hypothesized that PT renin-angiotensin system disruption would not only depress PT Na+ transporters but also impact downstream Na+ transporters. Using a mouse model in which the angiotensin type 1a receptor (AT1aR) is deleted specifically within the PT (AT1aR PTKO), we profiled the abundance of Na+ transporters, channels, and claudins along the nephron. Absence of PT AT1aR signaling was associated with lower abundance of PT transporters (Na+/H+ exchanger isoform 3, electrogenic Na+-bicarbonate cotransporter 1, and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated Na+-K+-2Cl− cotransporter, medullary Na+-K+-ATPase, phosphorylated NaCl cotransporter, and claudin 7) versus controls. However, transport activities of Na+-K+-2Cl− cotransporter and NaCl cotransporter (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on Na+ reabsorption in the PT at baseline and the associated influence on downstream Na+ transporters, highlighting the ability of the nephron to integrate Na+ transport along the nephron to maintain homeostasis. [ABSTRACT FROM AUTHOR]

Background: Treatment of heart failure with reduced ejection fraction (HFrEF) has been revolutionized by angiotensin receptor/neprilysin inhibitor (ARNI). ARNI has been shown to significantly reduce morbidity and mortality in a large, randomized controlled trial. However, real-world evaluation of ARNI with a diverse population is still limited.Methods: HFrEF patients receiving angiotensin receptor/neprilysin inhibitor (ARNI) or standard HF treatment at a university hospital in Thailand were prospectively followed-up from January 2015 to December 2019. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Survival analysis and the Cox proportional hazard model were used to compare clinical outcomes between the two groups.Results: During a follow-up period of 12 months, the primary outcome occurred in 10 patients in the ARNI group (11.5%) and 28 in the standard treatment group (28.0%) (hazard ratio 0.34; 95% CI: 0.15-0.80; p = 0.013). After adjustment for confounding factors, ARNI was significantly associated with a significant reduction in the primary outcome (HR 0.32, 95% CI: 0.13-0.82, p = 0.017). In addition, ARNI was also significantly associated with a decrease in the clinical signs and symptoms of HF, including dyspnea, orthopnea, and fatigue. Orthostatic hypotension was more frequently reported among the ARNI group than among the standard treatment group. The rates of target dose achievement were comparable between the two groups.Conclusion: In real-world practice, ARNI use was associated with a significant reduction in both clinical outcomes and symptom improvement, while orthostatic hypotension was more common in patients in the ARNI group than in patients in the standard treatment group. [ABSTRACT FROM AUTHOR]

Calcitriol, an active form of vitamin D, has immunomodulatory and anti-inflammatory properties. Vitamin D levels have inverse correlation with sepsis outcomes and obesity may aggravate the severity of the diseases. This study administered calcitriol to investigate its impact on sepsis-induced acute lung injury (ALI) in obese mice. Mice were fed a high-fat diet to induce obesity and were randomly assigned to control or sepsis groups, which were intravenously administered either saline (SS) or calcitriol (SD). Sepsis was induced by cecal ligation and puncture (CLP). Saline or calcitriol was injected 1 h after CLP via tail vein. Mice were sacrificed at either 12 or 24 h post-CLP and survival rates were observed. The results demonstrated that sepsis caused upregulation of inflammatory mediators and downregulation of renin-angiotensin system (RAS)-associated gene expressions in the lungs of obese mice. Cluster of differentiation 68 (CD68) expression and myeloperoxidase (MPO) activities also increased. Calcitriol treatment lowered expressions of blood and lung inflammatory mediators at 12 and/or 24 h after CLP. The RAS-proinflammatory-associated angiotensin type 1 receptor (AT1R) was lower while anti-inflammatory Mas receptor and AT2R expressions were higher at 12 h after CLP than those in the SS group. In addition, the SD group exhibited lower CD68 expression and MPO activity. Lower lung injury scores and higher survival rates were also noted in the SD group. The findings suggest that calcitriol treatment after sepsis induction upregulated RAS-associated anti-inflammatory pathway and decreased immune cell infiltration, which may have alleviated the severity of ALI of obese mice.

The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension.

Mohamed Ibrahim ElGhareeb,1 Mohamed Hamed Khater,1 Ahmed Fakhr,2 Hanaa Abd-Elftah Khedr3 1Dermatology and Venereology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 2Microbiology, Molecular Biology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 3Dermatology Department, Al Ahrar Hospital, Zagazig, EgyptCorrespondence: Mohamed Ibrahim ElGhareebDermatology and Venereology Department, Faculty of Medicine, Zagazig University, Zagazig, EgyptTel +20 109 290 7455Email moh_elghareeb@yahoo.comBackground: Psoriasis vulgaris is a chronic inflammatory and proliferative skin disease, characterized by the formation of itchy, erythematous skin patches or plaques. Patients with psoriasis are at an increased risk of developing metabolic syndrome, including obesity, hypertension, diabetes, and atherosclerosis. Recently, angiotensin II (Ang II) has been reported to be associated with the development of psoriasis. Ang II not only increases the blood pressure but is also a potent proinflammatory modulator and functions through interaction with angiotensin II type 1 receptor (AT1R). Moreover, it is hypothesized that the AT1R gene expression could be correlated with the severity of psoriasis and/or metabolic syndrome.Aim: We examined the association of Ang II type 1 receptor (AT1R) A1166C gene polymorphisms and metabolic syndrome with the severity of psoriasis.Patients and methods: The present case-control study included 25 patients with psoriasis vulgaris and 25 healthy subjects in Egypt. The psoriasis lesions in the patient group were assessed using the psoriasis area and severity index (PASI) score. The AT1R polymorphism A1166C (rs5186) was studied using restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) amplification of the gene from the whole blood sample in both groups. Serum lipid profile and blood sugar levels were assessed post 12 h and 8 h fasting, respectively, in both groups. The severity of metabolic syndrome was evaluated using the severity score.Results: The results of the present study demonstrated that the AT1R A1166C gene polymorphisms increased the risk of developing psoriasis in the Egyptian population. We found that 70% of patients with AC genotype and 100% of patients CC genotype reported a PASI score >20 and were considered to be severe cases with a statistically significant difference as compared with patients with AA genotype (p=0.003). In addition, a high statistically significant difference (p=0.001) existed among AT1R genotypes with respect to the percentage of metabolic syndrome in psoriasis patients. Similarly, a statistically significant difference (p=0.004) among AT1R genotypes with respect to metabolic score was found, with the highest level of score and percentage observed in patients with CC genotype than in patients with AC genotype. The lowest level was present among those with AA genotype.Conclusion: Patients with psoriasis expressing the C allele of AT1R1166 are susceptible to developing metabolic syndrome and have higher PASI scores as compared with patients carrying the A allele.Keywords: psoriasis, metabolic syndrome, angiotensin receptor, gene polymorphism

Activation of central AT1Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in deoxycorticosterone acetate (DOCA)-salt hypertension. TRV120027 (TRV027) is an AT1R-biased agonist that selectively acts through β-arrestin. We hypothesized that intracerebroventricular administration of TRV027 would ameliorate the effects of DOCA-salt. In a neuronal cell line, TRV027 induced AT1aR internalization through dynamin and clathrin-mediated endocytosis. We next evaluated the effect of chronic intracerebroventricular infusion of TRV027 on fluid intake. We measured the relative intake of water versus various saline solutions using a 2-bottle choice paradigm in mice subjected to DOCA with a concomitant intracerebroventricular infusion of either vehicle, TRV027, or losartan. Sham mice received intracerebroventricular vehicle without DOCA. TRV027 potentiated DOCA-induced water intake in the presence or absence of saline. TRV027 and losartan both increased the aversion for saline-an effect particularly pronounced for highly aversive saline solutions. Intracerebroventricular Ang (angiotensin) II, but not TRV027, increased water and saline intake in the absence of DOCA. In a separate cohort, blood pressure responses to acute intracerebroventricular injection of vehicle, TRV, or losartan were measured by radiotelemetry in mice with established DOCA-salt hypertension. Central administration of intracerebroventricular TRV027 or losartan each caused a significant and similar reduction of blood pressure and heart rate. We conclude that administration of TRV027 a selective β-arrestin biased agonist directly into the brain increases aversion to saline and lowers blood pressure in a model of salt-sensitive hypertension. These data suggest that selective activation of AT1R β-arrestin pathways may be exploitable therapeutically. [ABSTRACT FROM AUTHOR]

Background: The presence of autoantibodies to angiotensin 2 type 1 receptor (anti-AT1R) have been implicated in allograft pathobiology following organ transplantation. While the significance of these antibodies has been described in renal transplantation, relatively few studies have examined their frequency and clinical implications in heart transplant patients. Methods: We analyzed serum collected from 291 heart transplant recipients at the time of transplantation for the presence of anti-AT1R and repeated testing on serum collected from 176 of these patients following transplantation. Patients were followed for outcomes including overall survival, rejection episodes (acute cellular and antibody mediated), coronary allograft vasculopathy, and measures of allograft structure and cardiac function. Results: Anti-AT1R was detected in the serum of 165/291 patients pre-transplant and in 86/176 patients post-transplant. The detection of anti-AT1R (either at risk or positive) compared with no detection in serum of patients pre- or post-transplantation had no influence on 10-year survival (Log rank 0.061 and 0.228, detection pre- or post-transplant, respectively). Similarly, the detection of anti-AT1R had no influence on important clinical outcomes of heart transplantation including acute cellular rejection (ACR), antibody-mediated rejection (AMR) or cardiac allograft vasculopathy (CAV), left ventricular ejection fraction (LVEF) or left ventricular mass (LV-mass). Conclusions: The presence of anti-AT1R detected in patient serum samples by commercially available testing pre- or post- heart transplantation was not associated with clinically important outcomes including LV-mass, LVEF, ACR, AMR, CAV and overall survival. Our data brings into question the relevance of anti-AT1R testing as a risk factor or target for therapy among heart transplant recipients.

Abstract Angiotensin‐(1‐7), an endogenous agonist for the MasR, has been shown to interact with ang‐II AT1R and AT2R. Earlier we showed a physical and functional interaction between MasR and AT2R in response to their respective agonists ang‐(1‐7) and C21. Moreover, ang‐(1‐7) is cardio‐protective via AT1R and alters ang‐II function. Such complex nature of ang‐(1‐7) function is not clearly understood, particularly in relation to its functional interaction with these receptors. We tested how ang‐(1‐7) affects AT2R function by utilizing HK‐2 cells. The HK‐2 cells were treated with a wide range of concentrations of angiotensin receptor agonists. The generation of NO• in response to agonists was determined as a readout and subjected to Bliss definition (δ score) to assess the nature of functional interaction between these receptors. Preincubation with ang‐(1‐7) followed by incubation with endogenous AT1R/AT2R agonist ang‐II (δ = 162) or selective AT2R agonist C21 (δ = 304) synergized NO• formation. The synergism was also observed when the order of incubation with ang‐(1‐7)/C21 was reversed (δ = 484), but not when the cells were simultaneously incubated with a mixture of ang‐(1‐7) and C21 (δ = 76). The synergism with nonpeptidic MasR agonist AVE0991 followed by C21 (δ = 45) was minimal. Ligand binding experiment suggested the binding of ang‐(1‐7) with these three receptors. However, the synergism observed with ang‐(1‐7) and ang‐II/C21 was sensitive to the antagonists of AT2R (PD123319) and AT1R (candesartan), but not MasR (A779). Ang‐(1‐7) at lower concentrations synergies the AT2R function in an AT1R‐dependent but MasR‐independent manner. This phenomenon may have a physiological significance.

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.

Obesity and adipose tissue dysfunction are important risk factors for pancreatic cancer. Pancreatic cancer is one of the most lethal cancers globally. The renin-angiotensin system (RAS) is expressed in many tissues, including adipose tissue. Dysregulation of angiotensin II and angiotensin II receptors in adipose tissue through the activation of different signaling pathways leads to adipose tissue dysfunction, including insulin resistance, adipose tissue inflammation, adipocytokines secretion, and metabolic alterations. The pathogenesis of pancreatic cancer remains uncertain. However, there is evidence that dysregulation of local angiotensin II in adipose tissue that occurs in association with obesity is, in part, responsible for the initiation and progression of pancreatic cancer. Due to the role of local angiotensin II in the dysfunction of adipose tissue, angiotensin receptor blockers may be considered a new therapeutic strategy in the amelioration of the complications related to adipose tissue dysfunction and prevention of pancreatic cancer. This review aims to consider the biological roles of local angiotensin II and angiotensin II receptors in adipose tissue dysfunction to promote pancreatic cancer progression with a focus on adipose tissue inflammation and metabolic reprogramming., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

β-arrestins are a family of intracellular signaling proteins that play a key role in regulating the activity of G protein-coupled receptors. The angiotensin-II type 1 receptor is an important G protein-coupled receptor involved in the regulation of cardiovascular function and has been implicated in the progression of cardiovascular diseases. In addition to canonical G protein signaling, G protein-coupled receptors including the angiotensin-II type 1 receptor can signal via β-arrestin. Dysregulation of β-arrestin signaling has been linked to several cardiovascular diseases including hypertension, atherosclerosis, and heart failure. Understanding the role of β-arrestins in these conditions is critical to provide new therapeutic targets for the treatment of cardiovascular disease. In this review, we will discuss the beneficial and maladaptive physiological outcomes of angiotensin-II type 1 receptor-dependent β-arrestin activation in different cardiovascular diseases., Competing Interests: Disclosures None.

Angiotensin-(1-7), an endogenous agonist for the MasR, has been shown to interact with ang-II AT1R and AT2R. Earlier we showed a physical and functional interaction between MasR and AT2R in response to their respective agonists ang-(1-7) and C21. Moreover, ang-(1-7) is cardio-protective via AT1R and alters ang-II function. Such complex nature of ang-(1-7) function is not clearly understood, particularly in relation to its functional interaction with these receptors. We tested how ang-(1-7) affects AT2R function by utilizing HK-2 cells. The HK-2 cells were treated with a wide range of concentrations of angiotensin receptor agonists. The generation of NO• in response to agonists was determined as a readout and subjected to Bliss definition (δ score) to assess the nature of functional interaction between these receptors. Preincubation with ang-(1-7) followed by incubation with endogenous AT1R/AT2R agonist ang-II (δ = 162) or selective AT2R agonist C21 (δ = 304) synergized NO• formation. The synergism was also observed when the order of incubation with ang-(1-7)/C21 was reversed (δ = 484), but not when the cells were simultaneously incubated with a mixture of ang-(1-7) and C21 (δ = 76). The synergism with nonpeptidic MasR agonist AVE0991 followed by C21 (δ = 45) was minimal. Ligand binding experiment suggested the binding of ang-(1-7) with these three receptors. However, the synergism observed with ang-(1-7) and ang-II/C21 was sensitive to the antagonists of AT2R (PD123319) and AT1R (candesartan), but not MasR (A779). Ang-(1-7) at lower concentrations synergies the AT2R function in an AT1R-dependent but MasR-independent manner. This phenomenon may have a physiological significance. [ABSTRACT FROM AUTHOR]

Components of the renin-angiotensin system (RAS) situated within the carotid body or central nervous system may promote hypoxia-induced chemoreceptor reflex sensitization or central sleep apnea (CSA). We determined if losartan, an angiotensin-II type-I receptor (AT1R) antagonist, would attenuate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia, and consequently CSA severity. In a double-blind, randomized, placebo-controlled, crossover protocol, 14 men (age: 25 ± 2 years; BMI: 24.6 ± 1.1 kg/m2; means ± SEM) ingested 3 doses of either losartan (50 mg) or placebo every 8 h. Chemoreceptor reflex sensitivity was assessed during hypoxic and hyperoxic hypercapnic ventilatory response (HCVR) tests and during six-20s hypoxic apneas before and after 8 h of sleep in normobaric hypoxia (FIO2 = 0.135). Loop gain was assessed from a ventilatory control model fitted to the ventilatory pattern of CSA recorded during polysomnography. Prior to nocturnal hypoxia, losartan had no effect on either the hyperoxic (losartan: 3.6 ± 1.1, placebo: 4.0 ± 0.6 l/min/mmHg; P = 0.9) or hypoxic HCVR (losartan: 5.3 ± 1.4, placebo: 5.7 ± 0.68 l/min/mmHg; P = 1.0). Likewise, losartan did not influence either the hyperoxic (losartan: 4.2 ± 1.3, placebo: 3.8 ± 1.1 l/min/mmHg; P = 0.5) or hypoxic HCVR (losartan: 6.6 ± 1.8, placebo: 6.3 ± 1.5 l/min/mmHg; P = 0.9) after nocturnal hypoxia. Cardiorespiratory responses to apnea and participants’ apnea hypopnea indexes during placebo and losartan were similar (73 ± 15 vs. 75 ± 14 events/h; P = 0.9). Loop gain, which correlated with CSA severity (r = 0.94, P < 0.001), was similar between treatments. In summary, in young healthy men, hypoxia-induced CSA severity is strongly associated with loop gain, but the AT1R does not modulate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia.

Introduction: The European Society of Cardiology (ESC), Canadian Cardiovascular Society, and the American College of Cardiology Heart Failure (HF) guidelines all currently recommend the use of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) and Beta Blockers (BB) in the treatment of HF with a reduced ejection fraction (HFrEF). Newer medications targeting combining an ARB with a neprilysin inhibitor (ARNI) sacubitril/valsartan have shown benefits in mortality and can be used in place of an ACE inhibitor or an ARB. Additionally, dapagliflozin, a medication targeting the sodium-glucose cotransporter 2 (SGLT2) can be used in addition to current therapies.Areas Covered: This review provides a comprehensive analysis of the evidence around the new pharmacotherapies for HFrEF, specifically, sacubitril/valsartan and dapagliflozin. A comprehensive review of the literature using keywords such as heart failure with reduced ejection fraction, angiotensin receptor, neprilysin inhibitor, and sodium glucose transporter was conducted within the National Centre for Biotechnology Information (NCBI) and Google Scholar databases. The reference sections of articles were also examined to find additional articles.Expert Opinion: Sacubitril/valsartan and dapagliflozin both show marked benefits on mortality in HFrEF patients. More research needs to be conducted on the mechanisms of action on disease modification. [ABSTRACT FROM AUTHOR]

Components of the renin-angiotensin system (RAS) situated within the carotid body or central nervous system may promote hypoxia-induced chemoreceptor reflex sensitization or central sleep apnea (CSA). We determined if losartan, an angiotensin-II type-I receptor (AT1R) antagonist, would attenuate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia, and consequently CSA severity. In a double-blind, randomized, placebo-controlled, crossover protocol, 14 men (age: 25 ± 2 years; BMI: 24.6 ± 1.1 kg/m2; means ± SEM) ingested 3 doses of either losartan (50 mg) or placebo every 8 h. Chemoreceptor reflex sensitivity was assessed during hypoxic and hyperoxic hypercapnic ventilatory response (HCVR) tests and during six-20s hypoxic apneas before and after 8 h of sleep in normobaric hypoxia (F I O2 = 0.135). Loop gain was assessed from a ventilatory control model fitted to the ventilatory pattern of CSA recorded during polysomnography. Prior to nocturnal hypoxia, losartan had no effect on either the hyperoxic (losartan: 3.6 ± 1.1, placebo: 4.0 ± 0.6 l/min/mmHg; P = 0.9) or hypoxic HCVR (losartan: 5.3 ± 1.4, placebo: 5.7 ± 0.68 l/min/mmHg; P = 1.0). Likewise, losartan did not influence either the hyperoxic (losartan: 4.2 ± 1.3, placebo: 3.8 ± 1.1 l/min/mmHg; P = 0.5) or hypoxic HCVR (losartan: 6.6 ± 1.8, placebo: 6.3 ± 1.5 l/min/mmHg; P = 0.9) after nocturnal hypoxia. Cardiorespiratory responses to apnea and participants' apnea hypopnea indexes during placebo and losartan were similar (73 ± 15 vs. 75 ± 14 events/h; P = 0.9). Loop gain, which correlated with CSA severity (r = 0.94, P < 0.001), was similar between treatments. In summary, in young healthy men, hypoxia-induced CSA severity is strongly associated with loop gain, but the AT1R does not modulate chemoreceptor reflex sensitivity before or after 8 h of nocturnal hypoxia. [ABSTRACT FROM AUTHOR]

Introduction: The aims of this study were to assess the renal expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor in human type 2 diabetic nephropathy (DN).Materials and Methods: In total, 115 patients diagnosed with DN by renal biopsy were enrolled in this study. The protein expression levels of the AT1R, AT2R, and MAS receptors were assessed by immunohistochemistry.Results: The protein expression levels of AT1R, AT2R, and MAS receptor in the renal biopsy tissue were correlated with the pathologic classification of DN. Tubulointerstitial AT1R expression in patients of class IIb was significantly stronger than control samples (p < 0.05). Expression of AT2R and MAS receptors were highest with class IIb DN patients. When DN patients were treated with AT1R blocker (ARB), the expression of AT1R was downregulated (p < 0.05), and the MAS receptor was upregulated in tubular interstitial (p < 0.05).Conclusions: Our results directly observed that renal expression levels of AT1R increase during the early stages of DN, ARB reducing AT1R while increasing MAS receptor. Therefore, ARB should be used as soon as possible in patients with DN. [ABSTRACT FROM AUTHOR]

Purpose of the Review: The main goal of this article is to discuss how the development of state-of-the-art technology has made it possible to address fundamental questions related to how the renin-angiotensin system (RAS) operates within the brain from the neurophysiological and molecular perspective. Recent Findings: The existence of the brain RAS remains surprisingly controversial. New sensitive in situ hybridization techniques and novel transgenic animals expressing reporter genes have provided pivotal information of the expression of RAS genes within the brain. We discuss studies using genetically engineered animals combined with targeted viral microinjections to study molecular mechanisms implicated in the regulation of the brain RAS. We also discuss novel drugs targeting the brain RAS that have shown promising results in clinical studies and trials. Summary: Over the last 50 years, several new physiological roles of the brain RAS have been identified. In the coming years, efforts to incorporate cutting-edge technologies such as optogenetics, chemogenetics, and single-cell RNA sequencing will lead to dramatic advances in our full understanding of how the brain RAS operates at molecular and neurophysiological levels. [ABSTRACT FROM AUTHOR]

Background We have developed a peptide vaccine named ATRQβ‐001, which was proved to retard signal transduction initiated by angiotensin II (Ang II). Ang II was implicated in abdominal aortic aneurysm (AAA) progression, but whether the ATRQβ‐001 vaccine would prevent AAA is unknown. Methods and Results Ang II‐infused ApoE−/− mice and calcium phosphate‐induced AAA in C57BL/6 mice were used to verify the efficiency of ATRQβ‐001 vaccine in AAA. Results demonstrated that the vaccine effectively restrained the aneurysmal dilation and vascular wall destruction of aorta in both animal models, beyond anti‐hypertensive effects. In Ang II‐induced AAA vascular sections, Immunohistochemical staining showed that the vaccine notably constrained vascular inflammation and vascular smooth muscle cell (VSMC) phenotypic transition, concurrently reduced macrophages infiltration. In cultured VSMC, the anti‐ATR‐001 antibody inhibited osteopontin secretion induced by Ang II, thereby impeded macrophage migration while co‐culture. Furthermore, metalloproteinases and other matrix proteolytic enzymes were also found to be limited by the vaccine in vivo and in vitro. Conclusions ATRQβ‐001 vaccine prevented AAA initiation and progression in both Ang II and calcium phosphate‐induced AAA models. And the beneficial effects were played beyond decrease of blood pressure, which provided a novel and promising method to take precautions against AAA.

Background Previous studies demonstrated that angiotensin (Ang) III, not Ang II, is the predominant endogenous agonist for Ang type‐2 receptor (AT2R)‐induced natriuresis in normal rats, and that hypertensive 12‐week‐old spontaneously hypertensive rats (SHR) lack natriuretic responses to Ang III. This study tested whether prehypertensive SHR already have defective Ang III‐induced natriuresis and determined possible mechanisms. Methods and Results Female and male normotensive 4‐week‐old SHR and Wistar Kyoto rats were studied after 24‐hour systemic AT1R blockade. Left kidneys received 30 minute renal interstitial infusions of vehicle followed by Ang III (3.5, 7.0, 14, and 28 nmol/kg per min; each dose for 30 minutes). Right kidneys received vehicle infusions. In 4‐week‐old Wistar Kyoto rats, renal interstitial Ang III increased urine sodium (Na+) excretion but failed to induce natriuresis in 4‐week‐old SHR. Renal Ang III levels were similar between Wistar Kyoto rats and SHR, making increased Ang III degradation as a possible cause for defective natriuresis in SHR unlikely. In Wistar Kyoto rats, renal interstitial Ang III induced translocation of AT2Rs to apical plasma membranes of renal proximal tubule cells. Simultaneously, Ang III induced retraction of the major Na+ transporter Na+‐H+ exchanger‐3 (NHE‐3) from apical membranes and internalization of Na+/K+ATPase (NKA) from basolateral membranes of renal proximal tubule cells. Consistent with NHE‐3 and NKA retraction, Ang III increased pSer552‐NHE‐3 and decreased pSer23‐NKA. In contrast, in SHR, intrarenal Ang III failed to induce AT2R translocation, NHE‐3 or NKA retraction, pSer552‐NHE‐3 phosphorylation, or pSer23‐NKA dephosphorylation. Conclusions These results indicate impaired Ang III/AT2R signaling as a possible primary defect in prehypertensive SHR.

Background Angiotensin II type 1 receptor (AT1R) autoantibody (AT1‐AA) was first identified as a causative factor in preeclampsia. Unlike physiological ligand angiotensin II (Ang II), AT1‐AA can induce vasoconstriction in a sustained manner, causing a series of adverse effects, such as vascular injury and poor placental perfusion. However, its underlying mechanisms remain unclear. Here, from the perspective of AT1R internalization, the present study investigated the molecular mechanism of sustained vasoconstriction induced by AT1R autoantibody. Methods and Results In the current study, we used the vascular‐ring technique to determine that AT1‐AA‐positive IgG, which was obtained from the sera of preeclamptic patients, induced long‐term vasoconstriction in endothelium‐intact or endothelium‐denuded rat thoracic arteries. The effect was caused by prolonged activation of AT1R downstream signals in vascular smooth muscle cells, including Ca2+, protein kinase C, and extracellular signal‐regulated kinase 1 and 2. Then, using subcellular protein fractionation, cell surface protein biotinylation, and total internal reflection fluorescence, we found that AT1‐AA‐positive IgG resulted in significantly less AT1R internalization than in the Ang II treatment group. Moreover, through use of fluorescent tracing and bioluminescence resonance energy transfer, we found that AT1‐AA‐positive IgG cannot induce the recruitment of β‐arrestin1/2, which mediated receptor internalization. Then, the effect of sustained AT1R activation induced by AT1‐AA‐positive IgG was rescued by overexpression of β‐arrestin2. Conclusions These data suggested that limited AT1R internalization resulting from the inhibition of β‐arrestin1/2 recruitment played an important role in sustained vasoconstriction induced by AT1‐AA‐positive IgG, which may set the stage for avoiding AT1R overactivation in the management of preeclampsia.

Objective: Given the importance of knowing the effects of blood flow restriction (BFR) plus exercise training (BFR training) on the cardiovascular system, present study conducted to determine the effect of combination of BFR with low intensity endurance exercise on aorta of old rats. Methods: Animal groups were control (CTL), sham (Sh), BFR, exercise (Ex), sham + exercise (Sh + Ex), and BFR + exercise (BFR + Ex). BFR induced by partial closing of the bilateral femoral arteries and duration of exercise was 10 weeks. Results: BFR induced increasing of aorta wall thickness and decreasing its elastin/collagen ratio. Training alone increased the expression of apelin (P < 0.05) and angiotensin AT2 receptor (AT2R) (P < 0.01 versus CTL, Sh and P < 0.05 versus BFR groups) and the elastin/collagen ratio (P < 0.001) but, decreased the expression of angiotensin AT1 receptor (AT1R) (P < 0.01 versus CTL, Sh and BFR groups), the AT1R/AT2R ratio and the wall thickness (P < 0.001) of aorta. In Ex + BFR group, the expression of mentioned receptors increased and reached to more than levels of Ex groups, and the AT1R/AT2R ratio reduced in comparison with CTL, Sh and BFR and was higher than training groups (P < 0.5). Exercise also reversed the negative effect of BFR on elastin/collagen ratio and wall thickness. Conclusion: The beneficial effects of low intensity endurance exercise on aorta of aged male rats are conserved partially in presence of BFR.

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

We previously described a novel "chemogenetic" animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast Damino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [18F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract Objective Given the importance of knowing the effects of blood flow restriction (BFR) plus exercise training (BFR training) on the cardiovascular system, present study conducted to determine the effect of combination of BFR with low intensity endurance exercise on aorta of old rats. Methods Animal groups were control (CTL), sham (Sh), BFR, exercise (Ex), sham + exercise (Sh + Ex), and BFR + exercise (BFR + Ex). BFR induced by partial closing of the bilateral femoral arteries and duration of exercise was 10 weeks. Results BFR induced increasing of aorta wall thickness and decreasing its elastin/collagen ratio. Training alone increased the expression of apelin (P < 0.05) and angiotensin AT2 receptor (AT2R) (P < 0.01 versus CTL, Sh and P < 0.05 versus BFR groups) and the elastin/collagen ratio (P < 0.001) but, decreased the expression of angiotensin AT1 receptor (AT1R) (P < 0.01 versus CTL, Sh and BFR groups), the AT1R/AT2R ratio and the wall thickness (P < 0.001) of aorta. In Ex + BFR group, the expression of mentioned receptors increased and reached to more than levels of Ex groups, and the AT1R/AT2R ratio reduced in comparison with CTL, Sh and BFR and was higher than training groups (P < 0.5). Exercise also reversed the negative effect of BFR on elastin/collagen ratio and wall thickness. Conclusion The beneficial effects of low intensity endurance exercise on aorta of aged male rats are conserved partially in presence of BFR. Highlights • Aging is associated with aortic remodeling and dysfunction. • Aging is associated with intolerance of heavy physical activity. • BFR plus mild exercise is a suggested model for rebirth of muscle mass in elderly. • Old rats were subjected to BFR training for ten weeks. • BFR training improved the aortic histology, apelin and Ang II receptors balance. [ABSTRACT FROM AUTHOR]