scholarly journals Protective Role of the ACE2/Ang-(1–9) Axis in Cardiovascular Remodeling

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
María Paz Ocaranza ◽  
Jorge E. Jalil
Keyword(s):  
Heart Failure ◽  
Renin Angiotensin System ◽  
Organ Damage ◽  
Protective Role ◽  
Angiotensin System ◽  
Cardiovascular Remodeling ◽  
End Organ Damage ◽  
Cv Disease

Despite reduction in cardiovascular (CV) events and end-organ damage with the current pharmacologic strategies, CV disease remains the primary cause of death in the world. Pharmacological therapies based on the renin angiotensin system (RAS) blockade are used extensively for the treatment of hypertension, heart failure, and CV remodeling but in spite of their success the prevalence of end-organ damage and residual risk remain still high. Novel approaches must be discovered for a more effective treatment of residual CV remodeling and risk. The ACE2/Ang-(1–9) axis is a new and important target to counterbalance the vasoconstrictive/proliferative RAS axis. Ang-(1–9) is hydrolyzed slower than Ang-(1–7) and is able to bind the Ang II type 2 receptor. We review here the current experimental evidence suggesting that activation of the ACE2/Ang-(1–9) axis protects the heart and vessels (and possibly the kidney) from adverse cardiovascular remodeling in hypertension as well as in heart failure.

scholarly journals TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1100
Author(s):  
Aranzazu Santiago-Hernandez ◽  
Marta Martin-Lorenzo ◽  
Ariadna Martin-Blazquez ◽  
Gema Ruiz-Hurtado ◽  
Maria G Barderas ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Tricarboxylic Acid Cycle ◽  
Renin Angiotensin System ◽  
Roc Curves ◽  
Tca Cycle ◽  
Urinary Metabolites ◽  
Organ Damage ◽  
Fatty Acid Binding ◽  
Angiotensin System

Moderately increased albuminuria, defined by an albumin to creatinine ratio (ACR) > 30 mg/g, is an indicator of subclinical organ damage associated with a higher risk of cardiovascular and renal disease. Normoalbuminuric subjects are considered at no cardiorenal risk in clinical practice, and molecular changes underlying early development are unclear. To decipher subjacent mechanisms, we stratified the normoalbuminuria condition. A total of 37 hypertensive patients under chronic renin–angiotensin system (RAS) suppression with ACR values in the normoalbuminuria range were included and classified as control (C) (ACR < 10 mg/g) and high-normal (HN) (ACR = 10–30 mg/g). Target metabolomic analysis was carried out by liquid chromatography and mass spectrometry to investigate the role of the cardiorenal risk urinary metabolites previously identified. Besides this, urinary free fatty acids (FFAs), fatty acid binding protein 1 (FABP1) and nephrin were analyzed by colorimetric and ELISA assays. A Mann–Whitney test was applied, ROC curves were calculated and Spearman correlation analysis was carried out. Nine metabolites showed significantly altered abundance in HN versus C, and urinary FFAs and FABP1 increased in HN group, pointing to dysregulation in the tricarboxylic acid cycle (TCA) cycle and fatty acids β-oxidation. We showed here how cardiorenal metabolites associate with albuminuria, already in the normoalbuminuric range, evidencing early renal damage at a tubular level and suggesting increased β-oxidation to potentially counteract fatty acids overload in the HN range.

Abstract 336: Angiotensinogen Gene Polymorphism Confers a Multiple Risk Factor for Atherosclerosis and Its Susceptibility Traits

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Nduna Dzimiri ◽  
Samar Elhawari ◽  
Mohammed Al-Najai ◽  
Paul Muiya ◽  
Daisy Gueco ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Significant Risk ◽  
Renin Angiotensin System ◽  
Systemic Blood Pressure ◽  
Multiple Risk Factor ◽  
Systemic Blood ◽  
Angiotensin System ◽  
Cardiovascular Functions

Angiotensinogen (AGT) constitutes a pivotal component of the renin-angiotensin system which controls the systemic blood pressure and several other cardiovascular functions. In order to evaluate the role of the AGT gene polymorphism in atherosclerosis (CAD) and its risk factors, we first sequenced the gene in 200 individuals in search of informative SNPs. Of the >100 SNPs identified, we proceeded to evaluate the association of 8 variants in 3232 CAD cases versus 2292 angiographed controls by the Applied Biosystems real-time PCR system. Of the studied variants, the recessive mode of inheritance (TT) of rs3789679C>T [Odds ratio(95% Confidence Interval) = 1.23(1.05-1.45); p=0.012]; TT of rs699C>T [1.21(1.11-1.32); p<0.0001] as well as the dominant models (AG+GG) of rs5051A>G [1.22(1.10-1.37; p<0.0001) and AG+GG of rs2067853A>G [1.23(1.07-140);p=0.003] conferred risk for CAD. Interestingly, rs699 (p<0.0001), rs5051 (p=0.003) and rs2067853 (p=0.001) were equally implicated in hypertension, while the rs699 was further associated with hypercholesterolaemia (p=0.002) and hypertriglyceridaemia (p<0.0001), and the rs5051 was similarly associated with type 2 diabetes mellitus (T2DM) (p=0.011). One 8-mer haplotype from the 8 studied SNPs ACGGATAT (χ 2 =9.83; p=0.0017) and several of its variants, including the 7-mer ACGGATA (χ 2 =9.40; p=0.0022), 6-mer GGATAT (χ 2 =11.54; p=0.0007) and 5-mer GATAT (χ 2 =10.89; p=0.001) conferred significant risk for CAD. Furthermore, three 8-mer haploptypes GTGGGTGG (χ 2 =6.96; p=0.0083), ACGGGTAT (χ 2 =4.70; p=0.030) and GTAGGCGG (χ 2 =5.69; p=0.017) were associated with HTN. Similar trends were also observed for T2DM, obesity and hyperlipidaemia. These observations show that the AGT gene polymorphism confers a common risk for atherosclerosis and its major susceptibility traits.

scholarly journals Finerenone and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Type 2 Diabetes

Circulation ◽  
2020 ◽  
Author(s):  
Gerasimos Filippatos ◽  
Stefan D. Anker ◽  
Rajiv Agarwal ◽  
Bertram Pitt ◽  
Luis M. Ruilope ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renin Angiotensin System ◽  
Mineralocorticoid Receptor Antagonist ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
History Of

Background: The FIDELIO-DKD trial evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and CV outcomes. We report the effect of finerenone on individual CV outcomes and in patients with and without history of atherosclerotic CV disease (CVD). Methods: This randomized, double-blind, placebo-controlled trial included patients with T2D and urine albumin-to-creatinine ratio 30-5000 mg/g and an estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m 2 , treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite CV outcome included time to CV death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified CV analyses included analyses of the components of this composite and outcomes according to CVD history at baseline. Results: Between September 2015 and June 2018, 13,911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite CV outcome compared with placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.99; P=0.034), with no significant interaction between patients with and without CVD (HR, 0.85; 95% CI, 0.71-1.01 in patients with a history of CVD; HR, 0.86; 95% CI, 0.68-1.08 in patients without a history of CVD; P-value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone vs 0.8% with placebo in patients with CVD and 2.2% with finerenone vs 1.0% with placebo in patients without CVD). Conclusions: Among patients with CKD and T2D, finerenone reduced incidence of the composite CV outcome, with no evidence of differences in treatment effect based on pre-existing CVD status. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02540993 (Funded by Bayer AG)

The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice

2008 ◽  
Vol 294 (1) ◽  
pp. R26-R32 ◽  
Author(s):  
J. C. B. Ferreira ◽  
A. V. Bacurau ◽  
F. S. Evangelista ◽  
M. A. Coelho ◽  
E. M. Oliveira ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renin Angiotensin System ◽  
Collagen Content ◽  
Ang Ii ◽  
Male Adult ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Ras Activation

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking α2A and α2C adrenoceptor knockout (α2A/α2CARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, α2A/α2CARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, α2A/α2CARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT1 receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

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