Rennin Angiotensin Aldosterone System Research Articles

Curcumin as a Promising Therapy for COVID-19: A Review

The ongoing COVID-19 pandemic has spurred intense research efforts to identify effective therapeutic options. Among the potential candidates, curcumin, a naturally occurring polyphenol obtained from turmeric, has gained considerable attention due to its diverse pharmacological properties. This review examines the existing literature on curcumin’s potential as a new promising treatment for COVID-19. Curcumin demonstrates antiviral effects by modulating key signaling pathways for entry and multiplication of SARS-CoV-2 in host cells. It limits viral entry in host cells as it binds and inhibits S-protein, TMPRSS2, and ADAM17 enzymes required for cytoadherence and membrane fusion. It also downregulates SARS-CoV-2 replication by preventing the release of the viral genomic RNA into the cytoplasm from virus-containing vacuoles and subsequently inhibits enzymes required for viral replication. Rennin–angiotensin–aldosterone system (RAS) dysfunction, especially increased angiotensin-converting enzyme (ACE)-Angiotensin II-AT1R axis activity, is associated with prothrombotic state, acute respiratory distress syndrome, and lung injury in COVID-19 patients. Curcumin increases soluble ACE2 cellular ACE2 activity, restores RAS normal function, and mitigates these complications. Curcumin also exerts anti-inflammatory and immunomodulatory actions. It reduces the secretion of pro-inflammatory cytokines through inhibition of toll-like receptors (TLRs), namely, TLR2, TLR4, and TLR9, and enhances the production of anti-inflammatory cytokines like interleukin-10. In addition, it prevents the progression of tissue damage and inflammation by reactive oxygen species (ROS) through ROS scavenging enzymes. Due to its antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties, curcumin has emerged as an attractive candidate for combating various aspects of COVID-19 pathogenesis, such as excessive inflammation, oxidative stress, viral multiplication, and immune dysregulation. However, limited clinical evidence is currently available to support its efficacy, specifically against COVID-19. Thus, further research, including clinical trials, is warranted to evaluate curcumin’s therapeutic potential and determine its optimal dosage, formulation, and safety for COVID-19 patients. Overall, based on its favorable pharmacological properties and promising preclinical data, curcumin holds promise as a treatment for COVID-19, but its clinical utility requires further exploration.

Abstract 12379: AT1-AA (Angiotensin II Type 1 Receptor Autoantibody) Aggravates Abdominal Aortic Aneurysm Through Activating AT1R/Gq Allosterically

Background: Angiotensin II type 1 receptor (AT1R) is a key mediator of the rennin-angiotensin-aldosterone system (RAAS). Autoantibodies against AT1R (AT1-AA), as an activator of AT1R, was found in abdominal aortic aneurysm (AAA) related diseases, such as hypertension and atherosclerosis. However, the role of AT1-AA in AAA is still unclear. Methods: We used angiotensin II (AngII)-infused male ApoE -/- mice model of AAA. Ultrasonography measurement, histological assessment, western blot, qRT-PCR and RNA sequencing were used to assess the severity of AAA. Nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay, radio assay of receptors and homogeneous time resolved fluorescence (HTRF) were used to measure the activation feature of AT1R and the affinity of AT1R with AT1-AA or AngII. Results: AT1-AA increased the incidence of AAA (vehicle vs. AT1-AA: 47% vs. 81%; P<0.05), which can be attenuated by AT1R blocker Candesartan. Furthermore, AT1-AA greatly increased severity of AAA, due to augmenting the diameter of abdominal aorta and the degradation of elastin by enhancing the expression of MMP2/9 (matrix metalloproteinase) and the accumulation of inflammatory cells. And AT1-AA could induce phenotypic switch of smooth muscle cells. But AT1-AA does not increase the plasma level of AngII. Mechanically, AT1-AA enhanced AngII-induced recruitment of Gq, but not β-arrestin1/2. AT1-AA potentiated the AngII-mediated Gq-dependent inositol phosphate (EC50 shift=3.829 nM) and the activation of PKC and ERK1/2. The responses were abolished by AT1R blocker and Gq inhibitor. The affinity of AT1-AA for the AT1R in cells was calculated to be 75.49 ± 4.7 nM. AT1-AA cannot compete for the binding of AngII to AT1R. However, AT1-AA significantly potentiated the binding of AngII with AT1R allosterically (mean K D ± SEM: 34.11 ± 0.9765 nM at 0 nM AT1-AA vs. 25.63 ± 1.826 nM at 100 nM AT1-AA; p<0.05), without altering the maximum binding. Conclusion: AT1-AA, as an allosteric activator of AT1R, promotes AAA through increasing the affinity of AngII with AT1R and activating Gq biasedly.

BLOOD PRESSURE PROFILE IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Objective: High blood pressure (HBP) is often associated with chronic kidney disease (CKD). It can be a cause or a complication of the latter. The aim of this work was studying the clinical characteristics and the therapeutic modalities prescribed in our hypertensive patients monitored in nephrology consultation. Design and method: It was a retrospective descriptive study conducted at the nephrology consultation from January 2020 to January 2022. The stage of chronic kidney disease was defined according to the KDIGO classification. A therapeutic target achieved was defined by a Systolic Blood pressure<140 mmHg and a Disyslotic Blood Pressure<90 mmHg. Results: Our population included 53 hypertensive patients who were followed for chronic kidney disease. The mean age was 70.16 [46-90] with a M/F sex ratio of 1.3. The stage of chronic kidney disease was 1,2,3,4 and 5 in 2 patients (3.77%), 7 patients, (13.2%), 25 patients (47.16%), 8 patients (15.09%) and 11 patients (20.75%) respectively. Hypertension was classified as grade 1, 2 and 3 in 18 (33.16%), 6 (11.32%) and 3(5.6%) patients respectively. The mean systolic blood pressure in our patients was 137.55+/-21.54 mmHg and the mean diastolic was 78.62+/-11.37mmHg. Left ventricular hypertrophy on ultrasound was found in 4 patients (7.54%). Blood pressure was balanced in 42 (79.4%) patients, of whom 29 were on a calcium channel blocker alone or in dual therapy, 27 patients were on a combination containing a blocker of the rennin angiotensin aldosterone system, 17 patients were on beta blocker,14 patients were on dual therapy containing a loop diuretic and 13 patients were on a central antihypertensive. The therapeutic target was not reached in 11 patients, among whom there was a dietary deviation in 4 patients, nonadherence to treatment in 6 patients and sleep apnea in 1 patient. Five patients were in stage 4 and 5 of chronic kidney disease. Conclusions: Blood pressure control is an important part of the follow-up of hypertensive patients in nephrology. Hypertension can increase the morbidity and mortality of the chronic kidney disease.

Effect of lisinopril therapy on serum leptin, oxidative stress and C-reactive protein in hypertensive patients

The pathogenesis of essential hypertension through the interaction with elements of the rennin angiotensin aldosterone system is affected by oxidative stress and inflammation. The present study aimed to assess the effects of ACE-Inhibitor, lisinopril, on blood pressure, lipid profiles (total cholesterol, triglycerides, LDL and HDL), MDA, and TAS, hsCRP, and serum leptin levels n hypertensive patients. A case control study included 100 newly diagnosed mild to moderate hypertensive patients and another 100 apparently healthy aged and sex matched subjects as controls. The patients were treated with 10 mg lisinopril orally per day for three months’ duration. Venous blood sample was taken to test levels of MDA, GSH and TAS, hsCRP, lipid profiles and leptin in the serum before and after lisinopril therapy for both patients and controls. Systolic and diastolic blood pressure were also assessed before and after lisinopril therapy for both patients and controls. In hypertensive patients treated with lisinopril, markers of oxidative stress (MDA, TAS and GSH), high sensitive C-reactive protein and leptin were all found to be decreased significantly after drug treatment (p < 0.01). Lisinopril affectively lowered systolic and diastolic BP values (p < 0.01). A significant decrease in lipid profile (p < 0.01) with a significant increase in HDL-C and TAS levels (p < 0.01) were found in lisinopril treated group in comparison with their values before treatment. Lisinopril may be used as a treatment for high blood pressure, as well as for the insulin resistance, hyperleptinemic, and low-grade inflammatory states that are associated with the disease.

Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis

Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear. This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy.Methods:In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations.Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS.Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.

Systematic Understanding of the Mechanisms of Flos Chrysanthemi Indici-mediated Effects on Hypertension via Computational Target Fishing.

Hypertension-induced stroke and coronary artery disease are significant causes of global morbidity and mortality. Metabolic hypertension has recently become the leading cause of hypertension. Flos Chrysanthemi Indici (CIF) has a long history as a treatment of hypertension as part of traditional Chinese medicine. However, its mechanisms of activity remain largely unknown. This study was aimed to uncover the potential anti-hypertensive mechanisms of CIF based on network pharmacology. In this research, a systems pharmacology approach integrating the measurement of active compounds, target fishing, gene screening, Gene Ontology (GO) pathway analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) database analysis, and compound-target network construction were performed to explore the anti-hypertensive mechanisms of CIF. These studies revealed that 12 bioactive compounds in CIF had good druggability, 5 of which were flavonoids. After screening, 8 of those 12 bioactive compounds interacted with 118 hypertensionrelated target genes, which were mapped to 218 signal pathways. Network analysis showed that these targets were associated with improving insulin resistance, improving vascular function, inhibiting renninangiotensin- aldosterone system (RAAS), inhibiting the sympathetic nervous system (SNS) and regulating other physiological processes. In summary, CIF is predicted to target multiple proteins and pathways to form a network that exerts systematic pharmacological effects in order to regulate blood pressure and metabolic disorder.

Eplerenone: The Multifaceted Drug in Cardiovascular Pharmacology.

ABSTRACTConventionally, rennin–angiotensin–aldosterone system (RAAS) inhibition has focused on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and angiotensin receptor-neprilysin inhibitors (ARNI) are the latest addition to this armamentarium. However, mineralocorticoid receptor antagonists (MRAs) also constitute an integral part of this anti-RAAS brigade, which are perceived more often as diuretics and are often under prescribed in heart failure (HF) despite being universally advocated by all major guidelines. Apart from HF, they have also shown promise in the management of hypertension, post-myocardial infarction, and hyperaldosteronism. Eplerenone, Food and Drug Administration (FDA) approved in 2002, is an acceptable alternative to spironolactone due to its sparing androgenic effects. In two big pivotal trials in heart failure (EMPHASIS -HF) and post-myocardial infarction (EPHESUS), the drug has firmly shown a reduction in adverse cardiovascular events. It has an established place in the management of resistant hypertension too. In this article, we will discuss the role of RAAS and its pathophysiology, pitfalls of spironolactone, which led to success of its congener, eplerenone, major studies conducted on eplerenone, current role of eplerenone, and comparison of the two MRAs.

Effects of single and dual RAAS blockade therapy on progressive kidney disease transition to CKD in rats.

Ischemic reperfusion (I/R) is the primary cause of acute kidney injury (AKI) in hospitalized patients. Although AKI resolution occurs in few days, it predisposes kidneys to progressive renal injury. Previously, administration of rennin-angiotensin-aldosterone system (RAAS) blocker spironolactone in acute phase was reported to attenuate various manifestations of chronic kidney disease (CKD) in rats. The present study investigates the effects of RAAS blockade during progressive kidney disease (30 days onwards) on CKD outcomes in rodent model of I/R injury. CKD was induced by clamping both renal pedicles for 45 min followed by 90 days of reperfusion in rats. Single and dual RAAS blocker therapy was initiated at 30 days post-I/R injury and continued until the end of the study period. Evaluation of proteinuria and creatinine levels was done every 30 days in various study groups. Assessment of CKD was done by analyzing renal tissue oxidative stress, inflammatory biomarker levels, and histological changes after 90 days of I/R injury. After 90 days, I/R rat kidneys displayed hypertrophy, reduced body weight, increased oxidative stress, elevated inflammatory biomarker levels, and histological abnormalities such as glomerulosclerosis, mesangial expansion, and tubulointerstitial fibrosis. Treatment with losartan or spironolactone alone significantly reduced various CKD-associated features. Remarkably, combined treatment with dual RAAS blocker in low dose or high dose exhibited highest beneficial effects on various parameters in CKD model, with low-dose combination showing fewer side effects. Therefore, we propose that combined low-dose RAAS blockade therapy might serve as a better therapeutic approach for retarding progressive kidney disease transition to CKD.

The relationship among angiotensinogen genes polymorphisms and hs-CRP and coronary artery disease.

ObjectiveTo assess the association of gene polymorphisms of angiotensinogen (AGT), the key factor in rennin‐angiotensin‐aldosterone system (RAAS), with high‐sensitivity C‐reactive protein (hs‐CRP) and coronary artery disease (CAD).MethodsThe current study recruited the patients who were hospitalized and assessed by coronary angiography for suspected CAD. The patients with documented CAD served as CAD group (n = 492) while the patients without documented CAD (n = 87) served as control group. We compared laboratory data and CAD risk factors between the two groups. Furthermore, we analyzed the association of AGT M235T, G217A, G152A, G‐6A, A‐20C genotypes with coronary artery stenosis and in‐stent restenosis.ResultsThere were significantly differences between two patient groups in sex, smoking history, diabetes mellitus, carotid atherosclerosis, lower limb arteriosclerosis, hs‐CRP, blood glucose, and the level of high‐density lipoprotein (HDL; P < 0.05). In CAD group, hs‐CRP levels increased with increasing number of coronary artery branches (1, 2, or ≥3; P < 0.01), and Gensini integral was positively correlated with hs‐CRP levels (r = 0.361, P < 0.01). Frequencies of genotype and allele distribution in individual angiotensinogen loci (M235T, G217A, G152A, G‐6A, A‐20C) did not differ in two patient groups. Following stratification of patients according to hs‐CRP levels (<1 mg/L, 1‐3 mg/L, and >3 mg/L), the distribution frequency of allele M235T was statistically different among the groups (P < 0.05).ConclusionIn CAD patients, M235T among several AGT gene polymorphisms is associated with elevated hs‐CRP levels with AGT C allele as the significant factor for patients with hs‐CRP level of more than 1 mg/L.

Spironolactone alleviates diabetic nephropathy through promoting autophagy in podocytes

PurposePodocytes are terminally differentiated cells lining the Bowman’s capsule. Podocytes are critical for the proper glomerular filtration barrier function. At the same time, autophagy is crucial for maintaining podocyte homeostasis and insufficient autophagy could cause podocyte loss and proteinuria that is commonly observed in diabetic nephropathy (DN).MethodsIn this study, we investigated the role of spironolactone in podocyte loss and autophagy. DN model was established in male Sprague–Dawley rats using high-fat diet and low-dose streptozotocin. The impact of spironolactone on metabolic and biochemical parameters were tested by automatic biochemical analyzer. The angiotensin converting enzyme 1 and 2 (ACE1 and ACE2) and aldosterone were examined by ELISA. We examined the kidney histology and autophagy in podocytes by histochemical staining and electron microscopy. Podocyte loss and autophagy were analyzed by anti-NPHS2 and anti-WT1 as well as anti-Beclin1 and anti-LC3B, respectively.ResultsSpironolacton decreased the urinary albumin excretion, lipids and fasting glucose levels, and alleviated kidney damage. Further, spironolactone increased the expression of the podocyte-specific markers WT1 and NPHS2, as well as the autophagic markers Beclin1 and LC3B (P < 0.05). Additionally, spironolactone partially blocked the rennin angiotensin aldosterone system (RAAS) by regulating the ACE1, ACE2 and aldosterone levels.ConclusionsIn conclusion, spironolactone promoted autophagy in podocytes and further alleviated DN through partially blocking the RAAS.

Antifibrotic Roles of RAAS Blockers: Update.

The rennin–angiotensin–aldosterone system (RAAS) has been well documented in regulating blood pressure, fluid volume, and sodium balance. Overactivity of RAAS promotes both systemic and regional glomerular capillary hypertension, which could induce hemodynamic injury to the glomerulus, leading to kidney damage and renal fibrosis via profibrotic and proinflammatory pathway. Therefore, the use of RAAS inhibitors (i.e., ACEIs, ARBs, and MRAs) as the optional therapy has been demonstrated to prevent proteinuria, and kidney fibrosis and slow the decline of renal function effectively in the process of kidney disease during the last few decades. Recently, several new components of the RAAS have been discovered, including ACE2 and the corresponding ACE2/Ang (1-7)/Mas axis, which are also present in the kidney. Besides the classic RAAS inhibitors target the angiotensin-AT1-aldosterone axis, with the expanding knowledge about RAAS, a number of potential therapeutic targets in this system is emerging. Newer agents that are more specific are being developed. The present chapter outlines the insights of the RAAS agents (classic RAAS antagonists/the new RAAS drugs), and discusses its clinical application in the combat of renal fibrosis.

GW29-e0360 Correlation among Apnea-Hypopnea Index, Renin-Angiotensin-Aldosterone System and Blood Pressure in Hypertensive Patients combined with Obstructive Sleep Apnea

To explore the association between apnea-hypopnea index (AHI) and rennin-angiotensin-aldosterone system (RAAS), as well as that between AHI and blood pressure (BP), RAAS and BP in hypertensive patients combined with obstructive sleep apnea (OSA). 106 consecutive patients who were firstly diagnosed

PETANDA PERADANGAN hs CRP DENGAN HIPERTENSI

The major pathophysiologic mechanisms of hypertension include the activation of sympathetic nervous system and rennin–angiotensin–aldosterone system. Endothelial dysfunction, increased vascular reactivity, and vascular remodeling may cause that matter,rather than its consequences, of blood pressure elevation; increased vascular stiffness, which contributes to isolate systolic hypertensionin the elderly persons. Chronic low grade inflammation has been identified as an integral part in the pathogenesis of vascular disease.Inflammation may also be implicated in the development of hypertension. Several studies have demonstrated a significant relationshipbetween hs-CRP and stiffness of large arteries. If inflammation is truly linked to hypertension, then it would be reasonable to assume thatdrugs with anti-inflammatory actions may be able to arrest inflammation, improve endothelial function and lowering blood pressurein patients with hypertension. The aim of this cross sectional design study is to observe high sensitive C-reactive protein (hs-CRP)inflammatory markers in thirty five patients with hypertension. also want to know the present correlation between marker inflammationhs CRP with hypertension. With examine to some confounding factors as LDL, GDR and WBC. The results of this study showed that thereis no correlation between hs-CRP and hypertension, especially the duration of hypertension (r = 0.5 and p = 0.002). High degree ofhypertension was not followed by the increasing level of hs CRP.

Effect of Atractylodesmacrocephala rhizoma on isoproterenol‑induced ventricular remodeling in rats.

Myocardial infarction (MI) is the primary cause of ventricular remodeling (VR). The aim of the present study was to determine the effect of Atractylodismacrocephalae rhizoma (AMR) on VR induced by isoproterenol (ISO) in rats. Male Sprague Dawley rats were randomly divided into the normal control, ISO‑induced and AMR groups. Rats in the ISO‑induced and AMR groups were subcutaneously injected with 85mg/kg/day ISO for two consecutive days. Compared with the ISO‑induced group, AMR normalized the levels of hemodynamic parameters, markedly attenuated myocardial pathological damage, decreased the level of N‑terminal prohormone of brain natriuretic peptide, and inhibited cardiac hypertrophy and myocardial fibrosis. In addition, AMR inhibited oxidative stress and activation of the rennin‑angiotensin‑aldosterone system (RAAS) when compared with the ISO‑induced group. The results of the present study suggest that AMR may reverse VR via its antioxidative effect and inhibition of RAAS activation.

Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials

BackgroundHeart failure (HF) remains a significant cause of morbidity and mortality. Multiple trials over the past several years have examined the effects of both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet, there is still confusion regarding the relative efficacy of rennin-angiotensin-aldosterone system (RAAS) inhibition. Our study was conducted to assess efficacy of ACEIs and ARBs in reducing all-cause and cardiovascular mortality in heart failure patients.MethodsWe included randomized clinical trials compared ACEIs and ARBs treatment (any dose or type) with placebo treatment, no treatment, or other anti-HF drugs treatment, reporting cardiovascular or total mortality with an observation period of at least 12 months. Data sources included Pubmed, EMBASE, the Cochrane Central Register of Controlled Trials. Dichotomous outcome data from individual trials were analyzed using the risk ratio measure and its 95%CI with random-effects/ fixed-effects models. We performed meta-regression analyses to identify sources of heterogeneity. All-cause mortality and CV mortality were thought to be the main outcomes.ResultsA total of 47,662 subjects were included with a mean/median follow-up ranged from 12 weeks to 4.5 years. Of all 38 studies, 32 compared ACEIs with control therapy (included 13 arms that compared ACEIs with placebo, 10 arms in which the comparator was active treatment and 9 arms that compared ACEIs with ARBs), and six studies compared ARBs with placebo. ACEIs treatment in patients with HF reduced all-cause mortality to 11% (risk ratio (RR): 0.89, 95% confidence interval (CI): 0.83–0.96, p = 0.001) and the corresponding value for cardiovascular mortality was 14% (RR: 0.86, 95% CI: 0.78–0.94, p = 0.001). However, ARBs had no beneficial effect on reducing all-cause and cardiovascular mortality. In head-to-head analysis, ACEIs was not superior to ARBs for all-cause mortality and cardiovascular deaths.ConclusionsIn HF patients, ACEIs, but not ARBs reduced all-cause mortality and cardiovascular deaths. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.

Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population

Genetic, environmental and demographic factors contribute to the development of essential hypertension. Genetic polymorphism of Rennin-angiotensin-aldosterone system (RAAS) has been extensively studied to determine the genetic susceptibility to hypertension. The insertion/deletion (I/D) angiotensin converting enzyme (ACE) polymorphism has been established as a cardiovascular risk factor in some population, but its association with essential hypertension is controversial. This study sought to determine the association of I/D polymorphism of the ACE gene in south Indian essential hypertensive subjects. A total of 208 clinically diagnosed essential hypertensive patients without any associated diseases and 220 healthy control subjects were included in this study. Distribution and allelic frequency of Insertion (I) and Deletion (D) polymorphism at the 287 base pair Alu repeat sequence in the intron 16 of ACE gene were analyzed. The distribution of II, ID, DD genotypes of ACE gene was 28.3%, 32.6% and 38.9% respectively in essential hypertensive patients and to 53.6%, 26.3% and 20% in controls. The allele frequency for D allele is 0.58 in essential hypertension as compared to 0.34 of control subjects. The genotype and allele frequency of ACE gene polymorphism is significantly differed in patients when compared to controls. In conclusion, the I/D polymorphism of ACE gene is associated with Indian essential hypertension.

Case-control association study of polymorphisms in the angiotensinogen and angiotensin-converting enzyme genes and coronary artery disease and systemic artery hypertension in African-Brazilians and Caucasian-Brazilians.

The rennin-angiotensin-aldosterone system (RAAS) is a critical pathway in regulating blood pressure and salt/water homeostasis, possessing an intimate relationship with the development of systemic artery hypertension (SAH). Once hypertension is considered a risk factor for coronary artery disease (CAD), the RAAS is also related to this pathology. This investigation aimed to analyse if the frequencies of AGT M235T (rs699) and ACE I/D (rs4646994) polymorphisms are associated with CAD and SAH in African-Brazilians and Caucasian-Brazilians. In this study we analysed 714 subjects who underwent coronary angiography to detect obstructive lesions and CAD, as well as blood pressure measurement and SAH, grouped according to ethnicity: 266 African-Brazilians and 448 Caucasian-Brazilians. Among CAD and SAH cases and controls, the genotype and allele frequencies of ACE I/D polymorphism were similar in both ethnic groups. The AGT 235TT genotype and 235T allele frequencies were higher in SAH cases (32%, 54.7%) versus controls in Caucasian-Brazilians (19.8%, 46.4%; P = 0.038, P = 0.031, respectively). The AGT 235TT (OR = 1.8; P = 0.028) demonstrated to be an independent factor risk in a multivariate logistic regression increasing SAH risk in Caucasians but not in African-Brazilians. In summary, AGT M235T polymorphism was associated with SAH risk in Caucasian-Brazilians, and no association was detected with CAD. No association was also observed in ACE I/D polymorphism either in CAD or SAH in African-Brazilians and Caucasian-Brazilians.

Genetics of ischemic stroke: An Indian scenario.

Stroke, a heterogeneous multifactorial disorder, is known to be a major cause of death and adult disability within both the developed and developing countries. Approximately 85% of stroke cases are ischemic, whereas the remaining 15% are hemorrhagic. It is caused by multiple genetic factors, environmental factors, and interactions among these factors. Several candidate genes have been found to be associated with ischemic stroke. The most extensively studied genes include those involved in hemostasis, inflammation, nitric oxide production, homocysteine and lipid metabolism, and rennin-angiotensin-aldosterone system. Combined linkage/association studies have demonstrated that genes encoding phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) confer risk for stroke. Even though there is substantial evidence for the genetic basis of stroke as provided by the epidemiological data from twin- and family-based studies, the contribution of genetic factors identified till now is either not enough or very less to explain the entire spectrum of encountered phenomena associated with ischemic stroke. Till date, no genome-wide association studies (GWAS) have been carried out in India. We aim to extensively review the studies on candidate genes that may have potential applications in the early diagnosis, prevention, and treatment of ischemic stroke in the Indian population. This article further emphasizes the role of GWAS in ischemic stroke and the need for an extensive GWAS in the Indian population.

New Components of the Renin-Angiotensin-Aldosterone System and Oxidative Stress

Hypertension is a major risk factor of cardiovascular diseases (CVDs), and a most important health problem in developed countries. The rennin-angiotensin-aldosterone system (RAAS) plays a pivotal role in controlling blood pressure or hydro-electrolyte balance. Superoxide production by angiotensinâ i (Angâ i) of the classical RAAS pathway is one of the important mechanisms in pathogenesis of CVDs. But in the past decade, many new components of RAAS, such as novel axis consisting of the angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) (Ang-(1-7)), and the G protein-coupled receptor Mas, has emerged and complicated classical concept of RAAS and pathophysiology of CVDs. In this review we will summarize the recent findings about these new components of RAAS mainly from the viewpoint of molecular mechanism and oxidative stress.

Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity.

Hypogonadism in men is associated with an increased incidence of type 2 diabetes. Supplementation with testosterone has been shown to protect pancreatic β-cell against apoptosis due to toxic substances including streptozotocin and high glucose. One of the pathological mechanisms of glucose-induced pancreatic β-cell apoptosis is the induction of the local rennin-angiotensin-aldosterone system (RAAS). The role of testosterone in regulation of the pancreatic RAAS is still unknown. This study aims to investigate the protective action of testosterone against glucotoxicity-induced pancreatic β-cell apoptosis via alteration of the pancreatic RAAS pathway. Rat insulinoma cell line (INS-1) cells or isolated male mouse islets were cultured in basal and high-glucose media in the presence or absence of testosterone, losartan, and angiotensin II (Ang II), then cell apoptosis, cleaved caspase 3 expression, oxidative stress, and expression of angiotensin II type 1 receptor (AGTR1) and p47(phox) mRNA and protein were measured. Testosterone and losartan showed similar effects in reducing pancreatic β-cell apoptosis. Testosterone significantly reduced expression of AGTR1 protein in INS-1 cells cultured in high-glucose medium or high-glucose medium with Ang II. Testosterone decreased the expression of AGTR1 and p47(phox) mRNA and protein in comparison with levels in cells cultured in high-glucose medium alone. Furthermore, testosterone attenuated superoxide production when co-cultured with high-glucose medium. In contrast, when cultured in basal glucose, supplementation of testosterone did not have any effect on cell apoptosis, oxidative stress, and expression of AGT1R and p47(phox). In addition, high-glucose medium did not increase cleaved caspase 3 in AGTR1 knockdown experiments. Thus, our results indicated that testosterone prevents pancreatic β-cell apoptosis due to glucotoxicity through reduction of the expression of ATGR1 and its signaling pathway.