Angiotensin II-induced Hypertension Research Articles

RhoBTB1 reverses established arterial stiffness in angiotensin II-induced hypertension by promoting actin depolymerization.

Arterial stiffness predicts cardiovascular disease and all-cause mortality, but its treatment remains challenging. Mice treated with angiotensin II (Ang II) develop hypertension, arterial stiffness, vascular dysfunction, and a downregulation of Rho-related BTB domain–containing protein 1 (RhoBTB1) in the vasculature. RhoBTB1 is associated with blood pressure regulation, but its function is poorly understood. We tested the hypothesis that restoring RhoBTB1 can attenuate arterial stiffness, hypertension, and vascular dysfunction in Ang II–treated mice. Genetic complementation of RhoBTB1 in the vasculature was achieved using mice expressing a tamoxifen-inducible, smooth muscle–specific RhoBTB1 transgene. RhoBTB1 restoration efficiently and rapidly alleviated arterial stiffness but not hypertension or vascular dysfunction. Mechanistic studies revealed that RhoBTB1 had no substantial effect on several classical arterial stiffness contributors, such as collagen deposition, elastin content, and vascular smooth muscle remodeling. Instead, Ang II increased actin polymerization in the aorta, which was reversed by RhoBTB1. Changes in the levels of 2 regulators of actin polymerization, cofilin and vasodilator-stimulated phosphoprotein, in response to RhoBTB1 were consistent with an actin depolymerization mechanism. Our study reveals an important function of RhoBTB1, demonstrates its vital role in antagonizing established arterial stiffness, and further supports a functional and mechanistic separation among hypertension, vascular dysfunction, and arterial stiffness.

Aging Female Offspring Exposed to Maternal Hyperandrogenemia have Increased Renal Mitochondrial Content and Decreased Mitochondrial Reactive Oxygen Species

BackgroundPolycystic ovary syndrome (PCOS), the most common endocrine disorder in women, is characterized by hyperandrogenemia and elevated blood pressure. PCOS women who get pregnant have offspring with intrauterine growth restriction (IUGR). We use a clinically‐relevant rat model of PCOS, the hyperandrogenemic females (HAF), which develop most of the features of PCOS. Offspring of HAF dams are born with IUGR. We have previously shown that aging female HAF offspring are normotensive and are protected against angiotensin (Ang) II‐induced hypertension (HT). HT and Ang II‐induced HT have been shown to be associated with mitochondrial dysfunction. This study was performed to explore the renal mitochondrial function in aging female HAF offspring as a potential protective mechanism against Ang II HT.MethodsFemale Sprague Dawley rats were implanted with either 5α‐dihydrotestosterone (DHT; 7.5 mg/90 d, s.c.; HAF) or placebo pellets starting at 4 wks of age. HAF and controls were mated and allowed to deliver and lactate. Litters were culled to 4 males and 4 females on postnatal day 2. Female offspring were allowed to age to 16‐18 mos with no treatments, then euthanized and kidneys were collected for mitochondrial isolations (n = 3‐4, 1 rat/litter). Mitochondrial respiration and reactive oxygen species (mtROS) production were measured simultaneously by an Oroboros Fluorespirometer using glutamate/malate, succinate, oleate (long‐chain fatty acid; LCFA), or octanoate (medium chain fatty acid; MCFA). Complex IV activity, a marker of oxidative phosphorylation capacity, was measured by respirometry. Data were normalized to mitochondrial content using citrate synthase (CS) activity.ResultsDespite similar renal complex I and II‐driven respiration, renal LCFA (517 ± 24 vs 353 ± 34 nmol e‐/min/mg protein, p < 0.05) and MCFA (783 ± 58 vs 593 ± 58 nmol e‐/min/mg protein, p < 0.05) oxidation were significantly higher in HAF vs control offspring, respectively. Renal CS activity was significantly higher in HAF vs control offspring (884 ± 93 vs 616 ± 62 nmol/min/mg protein, respectively, p < 0.05). After normalization to CS activity, renal complex I and II‐driven respiration, LCFA and MCFA oxidation were similar between HAF and control offspring. Importantly, renal LCFA‐mediated ROS (4x10‐4 ± 7x10‐5 vs 8x10‐4 ± 2x10‐4 nmol e‐/CS activity, p < 0.05) and MCFA‐mediated ROS (6x10‐4 ± 10‐4 vs 10‐3± 2x10‐4 nmol e‐/CS activity, p < 0.05) production were lower in HAF vs control offspring, respectively. Renal complex I and II‐mediated ROS production and complex IV activity were similar between HAF and control offspring.ConclusionAging female HAF offspring have increased renal mitochondrial LCFA and MCFA oxidation that is due to increased mitochondrial content. They also have decreased mtROS production indicating a protection against renal mitochondria‐mediated oxidative stress compared to controls. Further studies are needed to determine if these differences have a mechanistic link to the protection against Ang II HT and whether there are changes in renal mitochondrial function following Ang II infusion in female HAF offspring.

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension.

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid–base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm

Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW = 290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50 = 0.25 μM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8 mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5 mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases.

Voluntary Exercise Prevents Hypertensive Response Sensitization Induced by Angiotensin II.

Exercise training has profound effects on the renin-angiotensin system, inflammatory cytokines and oxidative stress, all of which affect autonomic nervous system activity and regulate blood pressure (BP) in both physiological and pathophysiological states. Using the Induction-Delay-Expression paradigm, our previous studies demonstrated that various challenges (stressors) during Induction resulted in hypertensive response sensitization (HTRS) during Expression. The present study tested whether voluntary exercise would protect against subpressor angiotensin (ANG) II-induced HTRS in rats. Adult male rats were given access to either “blocked” (sedentary rats) or functional running (exercise rats) wheels for 12 weeks, and the Induction-Delay-Expression paradigm was applied for the rats during the last 4 weeks. A subpressor dose of ANG II given during Induction produced an enhanced hypertensive response to a pressor dose of ANG II given during Expression in sedentary rats in comparison to sedentary animals that received saline (vehicle control) during Induction. Voluntary exercise did not attenuate the pressor dose of ANG II-induced hypertension but prevented the expression of HTRS seen in sedentary animals. Moreover, voluntary exercise reduced body weight gain and feed efficiency, abolished the augmented BP reduction after ganglionic blockade, reversed the increased mRNA expression of pro-hypertensive components, and upregulated mRNA expression of antihypertensive components in the lamina terminalis and hypothalamic paraventricular nucleus, two key brain nuclei involved in the control of sympathetic activity and BP regulation. These results indicate that exercise training plays a beneficial role in preventing HTRS and that this is associated with shifting the balance of the brain prohypertensive and antihypertensive pathways in favor of attenuated central activity driving sympathetic outflow and reduced BP.

Blocking VCAM-1 Prevents Angiotensin II-Induced Hypertension and Vascular Remodeling in Mice.

Adhesion of monocytes to the vascular endothelium frequently leads to an inflammatory response, which contributes to hypertension and vascular remodeling. Vascular cellular adhesion molecule-1 (VCAM-1) plays an important role in leukocyte adhesion and migration during inflammatory diseases. However, its role in angiotensin (Ang) II -induced hypertension and vascular dysfunction remains largely unknown. Wild-type (WT) mice were administered a VCAM-1 neutralizing antibody (0.1 or 0.2 mg/mouse/day) or IgG control and then infused with Ang II (490 ng kg−1 min−1) or saline continuously for 14 days. Systolic blood pressure (SBP) was measured with a tail-cuff system, pathological changes in the aorta were assessed by histological staining, and vascular relaxation was analyzed an aortic ring assay. Our results indicated that compared with saline infusion, Ang II infusion significantly upregulated VCAM-1 expression in the mouse aorta and serum. Moreover, Ang II infusion markedly increased arterial hypertension, wall thickness, fibrosis, infiltration of Mac-2+ macrophages, reactive oxygen species (ROS) production and vascular relaxation dysfunction. Conversely, blockade of VCAM-1 with a neutralizing antibody substantially alleviated these effects. In vitro experiments further confirmed that the VCAM-1 neutralizing antibody inhibited Ang II-induced macrophage adhesion and migration and DNA damage and oxidative stress in endothelial cells (ECs). In conclusion, these results indicate that blockade of VCAM-1 exerts a protective effect against Ang II-induced arterial hypertension and dysfunction by regulating monocytes adhesion and infiltration into the endothelium and represents a novel therapeutic approach for hypertension.

Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner

Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wild-type mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.

Hdac8 Inhibitor Alleviates Transverse Aortic Constriction-Induced Heart Failure in Mice by Downregulating Ace1.

Background Heart failure is characterized by activation of the renin-angiotensin-aldosterone system, which is involved in the regulation of cardiac hypertrophy and hypertension. Recently, we reported that Hdac8 inhibition alleviates isoproterenol-induced and angiotensin II-induced cardiac hypertrophy or hypertension in mice. Here, the effect and regulatory mechanisms of the Hdac8 selective inhibitor PCI34051 on pressure overload-induced heart failure were examined. Methods and Results At week 6 posttransverse aortic constriction (TAC), mice were administered with PCI34051 (3, 10, or 30 mg/kg bodyweight/day) for 2 weeks. The therapeutic effects of PCI34051 on TAC-induced cardiac and lung hypertrophy were determined by examining the heart weight-to-bodyweight and lung weight-to-bodyweight ratios and the cross-sectional cardiomyocyte area. Echocardiography analysis revealed that PCI34051 mitigated TAC-induced decreased ejection fraction and fractional shortening. Additionally, the expression of Hdac8 was upregulated in the cardiac and pulmonary tissues of TAC mice. The expression levels of Ace1 and Agtr1 were upregulated, whereas those of Ace2 and Agtr2 were downregulated in TAC mice. PCI34051 treatment or Hdac8 knockdown alleviated inflammation as evidenced by Rela downregulation and Nfkbia upregulation in mice, as well as in cardiomyocytes, but not in cardiac fibroblasts. Hdac8 overexpression-induced Rela pathway activation was downregulated in Ace1 knockdown cells. Picrosirius red staining, real-time polymerase chain reaction, and western blotting analyses revealed that PCI34051 alleviated fibrosis and downregulated fibrosis-related genes. Moreover, PCI34051 or Hdac8 knockdown in rat cardiac fibroblasts alleviated cardiac fibrosis through the Tgfb1-Smad2/3 pathway. The results of overexpression and knockdown experiments revealed that Hdac8 and Ace1 promote inflammation and fibrosis. Conclusions Treatment with PCI34051 enhanced cardiac and lung functions in the TAC-induced heart failure mouse model. These data suggest that HDAC8 is a potential novel therapeutic target for heart failure accompanied by pathological lung diseases.

Phosphodiesterase 4D promotes angiotensin II-induced hypertension in mice via smooth muscle cell contraction

Hypertension is a common chronic disease, which leads to cardio-cerebrovascular diseases, and its prevalence is increasing. The cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway participates in multiple cardiovascular diseases. Phosphodiesterase (PDE) 4 has been shown to regulate PKA activity via cAMP specific hydrolysis. However, whether PDE4-cAMP-PKA pathway influences hypertension remains unknown. Herein, we reveal that PDE4D (one of PDE4 isoforms) expression is upregulated in the aortas of experimental hypertension induced by angiotensin II (Ang II). Furthermore, knockout of Pde4d in mouse smooth muscle cells (SMCs) attenuates Ang II-induced hypertension, arterial wall media thickening, vascular fibrosis and vasocontraction. Additionally, we find that PDE4D deficiency activates PKA-AMP-activated protein kinase (AMPK) signaling pathway to inhibit myosin phosphatase targeting subunit 1 (MYPT1)-myosin light chain (MLC) phosphorylation, relieving Ang II-induced SMC contraction in vitro and in vivo. Our results also indicate that rolipram, a PDE4 inhibitor, may be a potential drug for hypertension therapy.

Upregulation of miR-140-5p uncouples mitochondria by targeting Bcl-xL in vascular smooth muscle cells in angiotensin II-induced hypertension

ABSTRACT Angiotensin II–induced vascular smooth muscle cell (VSMC) remodeling and dysfunction is a major contributor to the development of hypertension. In spite of the low content of mitochondria and their low contribution to bioenergetics in VSMCs, recent studies have suggested that mitochondria play an important role in the regulation of VSMC function. However, the role of mitochondria in angiotensin II–induced VSMC dysfunction remains unknown. Here, we found that angiotensin II decreased the expression of Bcl-2-like protein 1 (Bcl-xL), a newly identified protein in inhibition of uncoupled proton flux in mitochondria through interaction with the β-subunit of ATP synthase, and uncoupled mitochondria in VSMCs both in vivo and in vitro. Overexpression of Bcl-xL restored the mitochondrial and VSMC function in response to angiotensin II treatment in vitro, suggesting that angiotensin II uncouples mitochondria through downregulation of Bcl-xL. Mechanistically, angiotensin II increased the expression of miR-140-5p, which targeted and downregulated Bcl-xL in VSMCs. Inhibition of miR-140-5p using antagomir-140-5p in vivo attenuated mitochondrial uncoupling and hypertension in angiotensin II-treated mice. These results suggested that upregulation of miR-140-5p uncouples mitochondria by targeting Bcl-xL in VSMCs in angiotensin II–induced hypertension, and miR-140-5p and Bcl-xL are potential targets for treatment of vascular dysfunction.

Gut microflora and metabolic syndrome: new insight into the pathogenesis of hypertension

Emerging evidences indicate that a microbial imbalance (dysbiosis) is linked to several diseases including metabolic cardiovascular diseases. A fecal microbiota transplantation from hypertensive human donor to germ-free mice caused blood pressure elevation. In addition, there is a report demonstrating that angiotensin II-induced hypertension and vascular dysfunction were attenuated in germ-free mice, suggesting that gut microbiome may mediate development of hypertension. Although detailed mechanism by which the dysbiosis induces an increased blood pressure remains unknown, changes in microbiome may modify host immune systems and induce inflammatory dysfunction in cardiovascular system, resulting in dysregulation of blood pressure. Some cohort studies demonstrated an association between a higher abundance of Streptococcaceae spp. and blood pressure. One recent report demonstrated that an increasing number of gram-positive Streptococcus was found in the feces of adult spontaneously hypertensive rats with an increased intestinal permeability. We hypothesized that increased bacterial toxin levels derived from gut Streptococcus may be a factor inducing blood pressure dysregulation. In this review, we discuss the possible role of microbiome in cardiovascular disease, especially hypertension.

Expression of arresten and its role in the heart of rats with angiotensin II-induced hypertension

Expression of arresten and its role in the heart of rats with angiotensin II-induced hypertension

CanstatinのN末端断片がangiotensin II誘発高血圧症モデルラットの左心肥大に及ぼす影響

CanstatinのN末端断片がangiotensin II誘発高血圧症モデルラットの左心肥大に及ぼす影響

Integrin CD11b Mediates Angiotensin Ii-Induced Hypertension and Vascular Injury by Regulating Macrophage Adhesion

Integrin CD11b Mediates Angiotensin Ii-Induced Hypertension and Vascular Injury by Regulating Macrophage Adhesion

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice.

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatics regulate inflammation through clearance of immune cells and excess interstitial fluid. Previously, we demonstrated increasing renal lymphangiogenesis prevents hypertension in mice. We hypothesized that targeted nanoparticle delivery of vascular endothelial growth factor-C (VEGF-C) to the kidney would induce renal lymphangiogenesis, lowering blood pressure in hypertensive mice. A kidney-targeting nanoparticle was loaded with a VEGF receptor-3-specific form of VEGF-C and injected into mice with angiotensin II-induced hypertension or LNAME-induced hypertension every 3 days. Nanoparticle-treated mice exhibited increased renal lymphatic vessel density and width compared to hypertensive mice injected with VEGF-C alone. Nanoparticle-treated mice exhibited decreased systolic blood pressure, decreased pro-inflammatory renal immune cells, and increased urinary fractional excretion of sodium. Our findings demonstrate that pharmacologically expanding renal lymphatics decreases blood pressure and is associated with favorable alterations in renal immune cells and increased sodium excretion.

Zebrafish Model to Study Angiotensin II-Mediated Pathophysiology.

Simple SummaryHypertension or high blood pressure is a long-term incurable clinical condition characterized by persistent high blood pressure in arteries. Constant pressure overload in the heart leads to cardiac remodeling involving hypertrophy, alteration of gene expression, extracellular matrix molecule deposition, and cardiac fibrosis. In the long term, if left untreated, it can lead to myocardial infarction. Zebrafish is a freshwater fish that has been proven to be a very beneficial model system to study development, regeneration, and human diseases in recent years. We propose in this study zebrafish as a model to study Angiotensin II-mediated (AngII) multifactorial pathophysiology. AngII is an effector molecule of the Renin–Angiotensin system (RAS), which plays a crucial role in hypertension in mammals. In our study, AngII was injected at regular time intervals for a period of time. Our results show that, similar to mammals, AngII induces fibrotic gene expression, collagen deposition, cardiomyocyte hypertrophy, and cardiac cell proliferation. Thus, we propose that zebrafish can prove to be a valuable model to study AngII-RAS pathway-mediated pathophysiology.Hypertension, a common chronic condition, may damage multiple organs, including the kidney, heart, and brain. Thus, it is essential to understand the pathology upon ectopic activation of the molecular pathways involved in mammalian hypertension to develop strategies to manage hypertension. Animal models play a crucial role in unraveling the disease pathophysiology by allowing incisive experimental procedures impossible in humans. Zebrafish, a small freshwater fish, have emerged as an important model system to study human diseases. The primary effector, Angiotensin II of the RAS pathway, regulates hemodynamic pressure overload mediated cardiovascular pathogenesis in mammals. There are various established mammalian models available to study pathophysiology in Angiotensin II-induced hypertension. Here, we have developed a zebrafish model to study pathogenesis by Angiotensin II. We find that intradermal Angiotensin II injection every 12 h can induce cardiac remodeling in seven days. We show that Angiotensin II injection in adult zebrafish causes cardiomyocyte hypertrophy and enhances cardiac cell proliferation. In addition, Angiotensin II induces ECM protein-coding gene expression and fibrosis in the cardiac ventricles. Thus, this study can conclude that Angiotensin II injection in zebrafish has similar implications as mammals, and zebrafish can be a model to study pathophysiology associated with AngII-RAS signaling.

Renal NOXA1/NOX1 Signaling Regulates Epithelial Sodium Channel and Sodium Retention in Angiotensin II-induced Hypertension.

Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension in chronic kidney disease patients. Genetic deletion of NOX activator 1 (Noxa1) subunit of NOX1 decreases ROS under pathophysiological conditions. Here, we investigated the role of NOXA1-dependent NOX1 activity in the pathogenesis of angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of abnormal renal function. Results: NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in Noxa1-/-versus wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS in kidney of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in Noxa1-deficient males and wild-type or Noxa1-/- females. In response to an acute salt load, Na+ excretion was similar in wild-type and Noxa1-/- mice before and 14 days after Ang II infusion. However, Na+ excretion was delayed after 1-2 days of Ang II in male wild-type versus Noxa1-/- mice. Ang II increased epithelial Na+ channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not Noxa1-/- mice. Aldosterone induced ROS levels and Noxa1 and Scnn1a expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by Noxa1 small-interfering RNA. Innovation and Conclusion: Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na+ reabsorption, leading to increased BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis. Antioxid. Redox Signal. 36, 550-566.

Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension

Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affect blood pressure. Recently we discovered a T-cell subset expressing ChAT (TChAT), whereby genetic ablation of ChAT in these cells produces hypertension, indicating that production of ACh by TChAT regulates blood pressure. Accordingly, we reasoned that increasing systemic ChAT concentrations might induce vasodilation and reduce blood pressure. To evaluate this possibility, recombinant ChAT was administered intraperitoneally to mice having angiotensin II-induced hypertension. This intervention significantly and dose-dependently decreased mean arterial pressure. ChAT-mediated attenuation of blood pressure was reversed by administration of the nitric oxide synthesis blocker l-nitro arginine methyl ester, indicating ChAT administration decreases blood pressure by stimulating nitic oxide dependent vasodilation, consistent with an effect of ACh on the endothelium. To prolong the half life of circulating ChAT, the molecule was modified by covalently attaching repeating units of polyethylene glycol (PEG), resulting in enzymatically active PEG-ChAT. Administration of PEG-ChAT to hypertensive mice decreased mean arterial pressure with a longer response duration when compared to ChAT. Together these findings suggest further studies are warranted on the role of ChAT in hypertension.

Hypotensive effect of Centella asiatica L. extract in acute Angiotensin II-induced hypertension

Centella asiatica L. (C.asiatica) is a plant with a hypotensive effect. Since this effect has several mechanism(s), therefore in the current study we investigated the effects of hydroalcoholic extract of C.asiatica on cardiovascular parameters in acute hypertensive rats. Animals were divided into four groups; 1) control, 2) Angiotensin II (AngII) that received (50 ng/kg) intravenously (i.v.), 3 and 4) two groups of C.asiatica extract (CA100, and CA200 mg/kg). In treated groups, 30 min after injection of the extract, AngII was injected. Cardiovascular parameters were recorded by the power lab system after the cannulation of the femoral artery. The maximum changes (∆) of systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were calculated and used for statistical analysis. In the AngII group, ΔSBP and ΔMAP significantly increased compared to the control group. The HR also decreased compared to the control group but it was not significant. In CA100+AngII group ΔSBP and ΔMAP significantly decreased compared to the AngII. The use of these doses of CA with AngІІ compared to AngІІ alone had a significant effect on the HR. In CA200+AngII group ΔSBP and ΔMAP significantly decreased compared to the AngII. The change of HR in this dose was not significant to the AngII. In a recent study, we concluded that C.asiatica decreased the cardiovascular responses in hypertensive rats received AngII. Also between two doses of C.asiatica did not observe any significant difference. Therefore, one of the most important hypotensive mechanism(s) of the considered plant can be the effect on Renin-angiotensin system.

Common Metabolites in Two Different Hypertensive Mouse Models: A Serum and Urine Metabolome Study.

Recent metabolomics studies have identified a wide array of microbial metabolites and metabolite pathways that are significantly altered in hypertension. However, whether these metabolites play an active role in pathogenesis of hypertension or are altered because of this has yet to be determined. In the current study, we hypothesized that metabolite changes common between hypertension models may unify hypertension’s pathophysiology with respect to metabolites. We utilized two common mouse models of experimental hypertension: L-arginine methyl ester hydrochloride (L-NAME)/high-salt-diet-induced hypertension (LSHTN) and angiotensin II induced hypertension (AHTN). To identify common metabolites that were altered across both models, we performed untargeted global metabolomics analysis in serum and urine and the resulting data were analyzed using MetaboAnalyst software and compared to control mice. A total of 41 serum metabolites were identified as being significantly altered in any hypertensive model compared to the controls. Of these compounds, 14 were commonly changed in both hypertensive groups, with 4 significantly increased and 10 significantly decreased. In the urine, six metabolites were significantly altered in any hypertensive group with respect to the control; however, none of them were common between the hypertensive groups. These findings demonstrate that a modest, but potentially important, number of serum metabolites are commonly altered between experimental hypertension models. Further studies of the newly identified metabolites from this untargeted metabolomics analysis may lead to a greater understanding of the association between gut dysbiosis and hypertension.