The renin angiotensin system (RAS) appears to influence male fertility at multiple levels. In this work, we analyzed the relationship between the RAS and DNA integrity. Fifty male volunteers were divided into two groups (25 each): control (DNA fragmentation ≤20%) and pathological (DNA fragmentation >20%) cases. Activities of five peptidases controlling RAS were measured fluorometrically: prolyl endopeptidase (which converts angiotensin [A] I and A II to A 1-7), neutral endopeptidase (NEP/CD10: A I to A 1-7), aminopeptidase N (APN/CD13: A III to A IV), aminopeptidase A (A II to A III) and aminopeptidase B (A III to A IV). Angiotensin-converting enzyme (A I to A II), APN/CD13 and NEP/CD10 were also assessed by semiquantitative cytometry and quantitative flow cytometry assays, as were the receptors of all RAS components: A II receptor type 1 (AT1R), A II receptor type 2 (AT2R), A IV receptor (AT4R or insulin-regulated aminopeptidase [IRAP]), (pro)renin receptor (PRR) and A 1-7 receptor or Mas receptor (MasR) None of the enzymes that regulate levels of RAS components, except for APN/CD13 (decrease in fragmented cells), showed significant differences between both groups. Micrographs of RAS receptors revealed no significant differences in immunolabeling patterns between normozoospermic and fragmented cells. Labeling of AT1R (94.3% normozoospermic vs 84.1% fragmented), AT4R (96.2% vs 95.3%) and MasR (97.4% vs 87.2%) was similar between the groups. AT2R (87.4% normozoospermic vs 63.1% fragmented) and PRR (96.4% vs 48.2%) were higher in non-fragmented spermatozoa. These findings suggest that fragmented DNA spermatozoa have a lower capacity to respond to bioactive RAS peptides.
Angiotensins ; DNA Fragmentation ; Humans ; Insulin ; Male ; Renin-Angiotensin System/physiology* ; Spermatozoa

The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
Angiotensins ; Asia ; Asian Continental Ancestry Group ; Enalapril ; Heart Failure ; Heart ; Hospitalization ; Humans ; Mortality ; Neprilysin ; Peptidyl-Dipeptidase A ; Prevalence ; Prospective Studies ; Renin-Angiotensin System ; Risk Factors ; Valsartan

No abstract available.
Angiotensins ; Muscle, Smooth ; Myocytes, Smooth Muscle

BACKGROUND AND OBJECTIVES: Angiotensin II (Ang II) has been suggested to accelerate vascular senescence, however the molecular mechanism(s) remain unknown. METHODS: We cultured human coronary artery smooth muscle cells (hCSMCs) and treated Ang II and/or fimasartan. Or we transfected adenoviral vectors expressing CYR61 (Ad-CYR61) or antisense CYR61 (Ad-As-CYR61). Cellular senescence was evaluated senescence-associated β-galactosidase (SA-β-gal) assay. The molecular mechanisms were investigated real-time PCR and western blots. RESULTS: SA-β-gal-positive cells significantly increased in Ang II-treated hCSMCs (5.77±1.43-fold compared with the control). The effect of Ang II was significantly attenuated by pretreatment with the Ang II type 1 receptor blocker, fimasartan (2.00±0.92-fold). The expression of both p53 and p16 senescence regulators was significantly increased by Ang II (p53: 1.39±0.17, p16: 1.19±0.10-fold vs. the control), and inhibited by fimasartan. Cysteine-rich angiogenic protein 61 (CYR61) was rapidly induced by Ang II. Compared with the control, Ad-CYR61-transfected hCSMCs showed significantly increased SA-β-gal-positive cells (3.47±0.65-fold). Upon transfecting Ad-AS-CYR61, Ang II-induced senescence (3.74±0.23-fold) was significantly decreased (1.77±0.60-fold). p53 expression by Ang II was significantly attenuated by Ad-AS-CYR61, whereas p16 expression was not regulated. Ang II activated ERK1/2 and p38 MAPK, which was significantly blocked by fimasartan. ERK and p38 inhibition both regulated Ang II-induced CYR61 expression. However, p53 expression was only regulated by ERK1/2, whereas p16 expression was only attenuated by p38 MAPK. CONCLUSIONS: Ang II induced vascular senescence by the ERK/p38 MAPK–CYR61 pathway and ARB, fimasartan, protected against Ang II-induced vascular senescence.
Aging ; Angiotensin II Type 1 Receptor Blockers ; Angiotensin II ; Angiotensins ; Blotting, Western ; Cell Aging ; Coronary Vessels ; Humans ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle ; p38 Mitogen-Activated Protein Kinases ; Real-Time Polymerase Chain Reaction ; Receptor, Angiotensin, Type 1

PURPOSE: Increased apoptosis was recently found in the hypertrophied left ventricle of spontaneously hypertensive rats (SHRs). Although the available evidence suggests that apoptosis can be induced in cardiac cells by various insults including pressure overload, cardiac apoptosis appears to result from an exaggerated local production of angiotensin in adult SHRs. Altered expressions of Bcl associated X (Bax), Bcl-2, chemokine receptor (CCR)-2, monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β1, phosphorylated extracellular signal-regulated kinases (PERK), and connexin 43 proteins, and kallikrein mRNA were investigated to explore the effects of losartan on the SHR model. METHODS: Twelve-week-old male rats were grouped as follows: control (C), SHR (hypertension: H), and losartan (L; SHRs were treated with losartan [10 mg/kg/day] for 5 weeks). Western blot and reverse transcription polymerase chain reaction assays were performed. RESULTS: Expression of Bax, CCR-2, MCP-1, TGF-β1, PERK, and connexin 43 proteins, and kallikrein mRNA was significantly increased in the H group compared to that in the C group at weeks 3 and 5. Expression of Bax, CCR-2, MCP-1, TGF-β1, and connexin 43 proteins and kallikrein mRNA was significantly decreased after losartan treatment at week 5. PERK protein expression was significantly decreased after losartan treatment at weeks 3 and 5. Bcl-2 protein expression was significantly decreased in the H group compared to that in the C group at weeks 3 and 5. CONCLUSION: Losartan treatment reduced expression of Bax, CCR-2, MCP-1, TGF-β1, PERK, and connexin 43 proteins, and kallikrein mRNA in SHRs, along with decreased inflammation and apoptosis.
Adult ; Angiotensins ; Animals ; Apoptosis ; Blotting, Western ; Connexin 43 ; Extracellular Signal-Regulated MAP Kinases ; Gene Expression ; Heart Ventricles ; Humans ; Inflammation ; Kallikreins ; Losartan ; Male ; Monocytes ; Polymerase Chain Reaction ; Rats ; Rats, Inbred SHR ; Reverse Transcription ; RNA, Messenger ; Transforming Growth Factors

Angiotensin II type 1 receptor (AT1R) antibodies directly injure endothelial and vascular smooth muscle cells by activating transcription factors associated with proinflammatory responses. Previous studies have shown that AT1R antibodies are associated with allograft rejection and decreased graft survival in kidney transplantation. Development of enzyme-linked immunosorbent assay has facilitated semiquantitative detection of AT1R antibodies. Assessing AT1R antibodies along with donor specific human leukocyte antigen antibodies may have potential to identify patients with possible risk for allograft injury and improve overall outcomes. In this review, we summarize recent clinical studies about AT1R antibodies in kidney transplantation and provide perspectives for future research area.
Activating Transcription Factors ; Allografts ; Angiotensin II ; Angiotensins ; Antibodies ; Enzyme-Linked Immunosorbent Assay ; Graft Survival ; Humans ; Kidney Transplantation ; Kidney ; Leukocytes ; Muscle, Smooth, Vascular ; Receptor, Angiotensin, Type 1 ; Tissue Donors ; Transplantation

PURPOSE: Statins, metformin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been suggested for treating age-related macular degeneration (AMD) due to their pleiotropic effects. Therefore, we investigated whether these drugs prevent AMD. MATERIALS AND METHODS: We conducted a nested case-control study using the Korean National Health Insurance Service database. Using risk-set sampling of age, sex, cohort entry date, and follow-up duration, we identified incident patients with AMD and 10 matching controls in cohorts with diabetes mellitus or cardiovascular diseases. Exposure was assessed within one year before the index date using patient prescription records. We conducted conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between cardiovascular medications and AMD. RESULTS: Our study included 2330 cases and 23278 controls from a cohort of 231274 patients. The ORs (95% CI) for AMD occurrence in users prescribed with statins, metformin, ACE inhibitors, and ARBs were 1.12 (0.94–1.32), 1.15 (0.91–1.45), 0.90 (0.61–1.34), and 1.21 (1.05–1.39), respectively. A duration-response was not observed. CONCLUSION: Statins, metformin, ACE inhibitors, and ARBs did not inhibit AMD in elderly patients. The absence of a duration-response supports the lack of a causal relationship.
Aged ; Angiotensin II ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Cardiovascular Diseases ; Case-Control Studies ; Cohort Studies ; Diabetes Mellitus ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Logistic Models ; Macular Degeneration ; Metformin ; National Health Programs ; Odds Ratio ; Prescriptions ; Receptors, Angiotensin

BACKGROUND AND OBJECTIVES: Human amniotic fluid-derived mesenchymal stem cells (AF-MSCs) may be a valuable source for cardiovascular tissue engineering and cell therapy. The aim of this study is to verify angiotensin II and transforming growth factor-beta 1 (TGF-β1) as potential cardiomyogenic differentiation inducers of AF-MSCs. METHODS AND RESULTS: AF-MSCs were obtained from amniocentesis samples from second-trimester pregnant women, isolated and characterized by the expression of cell surface markers (CD44, CD90, CD105 positive; CD34 negative) and pluripotency genes (OCT4, SOX2, NANOG, REX1). Cardiomyogenic differentiation was induced using different concentrations of angiotensin II and TGF-β1. Successful initiation of differentiation was confirmed by alterations in cell morphology, upregulation of cardiac genes-markers NKX2-5, TBX5, GATA4, MYH6, TNNT2, DES and main cardiac ion channels genes (sodium, calcium, potassium) as determined by RT-qPCR. Western blot and immunofluorescence analysis revealed the increased expression of Connexin43, the main component of gap junctions, and Nkx2.5, the early cardiac transcription factor. Induced AF-MSCs switched their phenotype towards more energetic and started utilizing oxidative phosphorylation more than glycolysis for energy production as assessed using Agilent Seahorse XF analyzer. The immune analysis of chromatin-modifying enzymes DNMT1, HDAC1/2 and Polycomb repressive complex 1 and 2 (PRC1/2) proteins BMI1, EZH2 and SUZ12 as well as of modified histones H3 and H4 indicated global chromatin remodeling during the induced differentiation. CONCLUSIONS: Angiotensin II and TGF-β1 are efficient cardiomyogenic inducers of human AF-MSCs; they initiate alterations at the gene and protein expression, metabolic and epigenetic levels in stem cells leading towards cardiomyocyte-like phenotype formation.
Amniocentesis ; Amniotic Fluid ; Angiotensin II ; Angiotensins ; Blotting, Western ; Calcium ; Cell Differentiation ; Cell- and Tissue-Based Therapy ; Chromatin ; Chromatin Assembly and Disassembly ; Connexin 43 ; Epigenomics ; Female ; Fluorescent Antibody Technique ; Gap Junctions ; Glycolysis ; Histones ; Humans ; Ion Channels ; Mesenchymal Stromal Cells ; Muscle Cells ; Oxidative Phosphorylation ; Phenotype ; Polycomb Repressive Complex 1 ; Pregnant Women ; Smegmamorpha ; Stem Cells ; Tissue Engineering ; Transcription Factors ; Up-Regulation

BACKGROUND: There have been few studies to evaluate the prognostic implications of guideline-directed therapy according to the temporal course of heart failure. This study assessed the relationship between adherence to guideline-directed therapy at discharge and 60-day clinical outcomes in de novo acute heart failure (AHF) and acute decompensated chronic heart failure (ADCHF) separately. METHODS: Among 5,625 AHF patients who were recruited from a multicenter cohort registry of Korean Acute Heart Failure, 2,769 patients with reduced ejection fraction were analyzed. Guideline-directed therapies were defined as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), β-blocker, and mineralocorticoid receptor antagonist. RESULTS: In de novo AHF, ACEI or ARB reduced re-hospitalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.34–0.95), mortality (HR, 0.41; 95% CI, 0.24–0.69) and composite endpoint (HR, 0.52; 95% CI, 0.36–0.77) rates. Beta-blockers reduced re-hospitalization (HR, 0.62; 95% CI, 0.41–0.95) and composite endpoint (HR, 0.65; 95% CI, 0.47–0.90) rates. In ADCHF, adherence to ACEI or ARB was associated with only mortality and β-blockers with composite endpoint. CONCLUSION: The prognostic implications of adherence to guideline-directed therapy at discharge were more pronounced in de novo heart failure. We recommend that guideline-directed therapy be started as early as possible in the course of heart failure with reduced ejection fraction.
Angiotensins ; Cohort Studies ; Heart Failure ; Heart ; Humans ; Mortality ; Receptors, Mineralocorticoid

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are the first choice for the treatment of acute myocardial infarction (AMI), and angiotensin receptor blockers (ARBs) should be considered in patients intolerant to ACEIs. Although previous studies support the use of ARBs as an alternative to ACEIs, these studies showed inconsistent results. The objective of this study was to demonstrate the clinical impact of ARBs as an alternative to ACEIs in patients with AMI undergoing percutaneous coronary intervention (PCI). METHODS: The CardiOvascular Risk and idEntificAtion of potential high-risk population in AMI (COREA-AMI) registry enrolled all consecutive patients with AMI undergoing PCI. The primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization due to heart failure. RESULTS: Of the 3,328 eligible patients, ARBs replaced ACEIs in 816 patients, while 824 patients continued to use ACEIs and 826 patients continued to use ARBs. The remaining 862 patients did not receive ACEIs/ARBs. After the adjustment with inverse probability weighting, the primary endpoints in the first groups were similar (7.5% vs. 8.0%, hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.75–1.05; P = 0.164). Composite events were less frequent in the ACEI to ARB group than no ACEI/ARB group (7.5% vs. 11.8%, HR, 0.76; 95% CI, 0.64–0.90; P = 0.002). CONCLUSION: The alternative use of ARBs following initial treatment with ACEIs demonstrates comparable clinical outcomes to those with continued use of ACEIs and is associated with an improved rate of composite events compared to no ACEI/ARB use in patients with AMI undergoing PCI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02385682
Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Heart Failure ; Hospitalization ; Humans ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Stroke