angiotensin-i and Atrial-Remodeling

Atrial fibrillation (AF) is a significant cause of morbidity and mortality as well as a public health burden considering the high costs of AF-related hospitalizations. Pre-clinical and clinical evidence showed a potential role of the renin angiotensin system (RAS) in the etiopathogenesis of AF. Among RAS mediators, angiotensin II (AII) and angiotensin 1-7 (A1-7) have been mostly investigated in AF. Specifically, the stimulation of the pathway mediated by AII or the inhibition of the pathway mediated by A1-7 may participate in inducing and sustaining AF. In this review, we summarize the evidence showing that both RAS pathways may balance the onset of AF through different biological mechanisms involving inflammation, epicardial adipose tissue (EAT) accumulation, and electrical cardiac remodeling. EAT is a predictor for AF as it may induce its onset through direct (infiltration of epicardial adipocytes into the underlying atrial myocardium) and indirect (release of inflammatory adipokines, the stimulation of oxidative stress, macrophage phenotype switching, and AF triggers) mechanisms. Classic RAS blockers such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may prevent AF by affecting the accumulation of the EAT, representing a useful therapeutic strategy for preventing AF especially in patients with heart failure and known left ventricular dysfunction. Further studies are necessary to prove this benefit in patients with other cardiovascular diseases. Finally, the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.

Topics: Angiotensin I; Angiotensin II; Atrial Fibrillation; Atrial Remodeling; Humans; Peptide Fragments

Topics: Angiotensin I; Angiotensin II; Animals; Anti-Arrhythmia Agents; Atrial Appendage; Atrial Fibrillation; Atrial Remodeling; Cell Line, Tumor; Focal Adhesion Kinase 1; Humans; Hydrostatic Pressure; Mice; Myocytes, Cardiac; Peptide Fragments; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; src-Family Kinases; Up-Regulation; Valsartan

To investigate changes in the angiotensin converting enzyme 2 (ACE2) and angiotensin (1-7) [Ang (1-7)] and to explore the role of ACE2-Ang (1-7)-Mas receptor axis in hypertension with heart failure with preserved ejection fraction (HFPEF).
 Methods: A total of 70 patients with primary hypertension and preserved left ventricular ejection fraction (LVEF>50%) were recruited and patients were divided into a hypertension group (HBP) and a heart failure with preserved ejection fraction group (HFpEF) according to the diagnostic criteria of HFpEF. Thirty-five healthy participants were selected randomly as a control group. Enzyme linked immunosorbent assays (ELISA) method was used to detect concentration of Ang (1-7), ACE2, angiotensin II (Ang II), brain natriuretic peptide (BNP) in plasma. Male Sprague- Dawley (SD) rats was randomly divided into 2 groups: An HFpEF group (n=16) and a sham group (n=8). Rats (n=8) in the AAC group were given Ang (1-7) [0.5 mg/(kg.d), intraperitoneally] for 6 weeks, and the rest were given equal dose normal saline. Then all the rats were killed, and the hearts were taken out for hematoxylineosin (HE) staining. The protein expressions of angiotensin converting enzyme (ACE), ACE2, and Mas receptor were detected by Western blot.
 Results: The BNP and Ang II were significantly increased in the HBP group and the HFpEF group compared with the control group (P<0.01). There were not significantly different in levels of ACE2 and Ang (1-7) between the HBP group and control group (P>0.05), whereas those levels were significantly increased in the HFpEF group compared with the HBP group and control group (P<0.01). HE staining showed obvious hypertrophy of myocardial cell in the AAC group compared with the sham group. Hypertrophy of myocardial cell in the AAC+Ang (1-7) group was significantly higher than that in the AAC group. Expressions of ACE, ACE2, and Mas receptor proteins were significantly higher in the AAC group than those in the sham group (P<0.05), while the expressions of ACE2 and Mas receptor proteins in the AAC+Ang (1-7) group were significantly higher than those in the AAC group (P<0.05). There was no significant difference in the ACE protein expression between groups (P>0.05).
 Conclusion: ACE2 and Ang (1-7) are important predictive factors for the severity of heart failure and myocardial remodeling of HFpEF with hypertension; ACE2-Ang (1-7)-Mas receptor axis may play a protective role in preventing myocardial remodeling in HFpEF wi. 目的：探讨高血压射血分数保留心力衰竭(以下简称心衰)中血管紧张素转化酶(angiotensin converting enzyme，ACE)2、血管紧张素(1-7)[angiotensin (1-7)，Ang (1-7)]的变化及ACE2-Ang (1-7)-Mas受体轴在高血压射血分数保留心衰(heart failure with preserved ejection fraction，HFpEF)中的作用。方法：1)入选原发性高血压患者70例，心脏彩超检测左室射血分数(left ventricular ejection fraction，LVEF)≥50%，根据HFpEF的诊断标准将高血压患者分为单纯高血压(hypertension，HBP)组和高血压HFpEF组；同时入选35例健康体检者作为正常对照组(Control)。采用酶联免疫吸附测定法(enzyme linked immunosorbent assays，ELISA)检测各组血浆中ACE2，Ang (1-7)，血管紧张素II(angiotensin II，Ang II)及脑利钠肽(brain natriuretic peptide，BNP)水平。2)选取雄性SD大鼠24只，随机选取8只作为假手术组(Sham)，16只SD大鼠行腹主动脉缩窄术(abdominal aortic constriction，AAC)建立HFpEF模型组，后将HFpEF模型组SD大鼠随机分为两组(n=8)：一组于腹腔内注射Ang (1-7)0.5 mg/(kg.mg)作为Ang (1-7)干预组；另一组于腹腔内注射等剂量生理盐水(AAC组)。干预6周后处死所有大鼠，对心脏标本行苏木精-伊红(hematoxylineosin，HE)染色，采用Western印迹法测定心肌组织中ACE，ACE2及Mas受体蛋白表达水平。结果：HBP组及高血压HFpEF组的BNP和Ang II均较Control组明显增高(P<0.01)；HBP组的ACE2，Ang (1-7)与Control组比较，差异无统计学意义(P>0.05)，而高血压HFpEF组ACE2和Ang (1-7)较HBP组及Control组均明显升高(P<0.01)。HE染色结果显示AAC组的心肌细胞较Sham组明显肥大，而Ang (1-7)干预组的心肌细胞肥大程度较AAC组减轻，AAC组的ACE2，ACE及Mas受体蛋白表达水平较Sham组均明显升高(P<0.05)，Ang (1-7)干预组ACE2和Mas受体表达水平较AAC组明显升高(P<0.05)，而ACE表达水平未受影响(P>0.05)。结论：ACE2和Ang (1-7)参与高血压HFpEF的发生发展过程，对高血压HFpEF的心衰和心肌重构的严重程度有重要预测价值；ACE2-Ang (1-7)-Mas受体轴可能在抑制高血压HFpEF心肌重构中起保护作用。.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Atrial Remodeling; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Heart Failure; Humans; Hypertension; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

Activation of the renin-angiotensin system plays an important role in atrial electrical remodeling; angiotensin-(1-7) (Ang-(1-7)) counterbalances the actions of angiotensin II. The aim of this study was to determine the effects of Ang-(1-7) on cardiac sodium current (INa ) in a canine model of atrial tachycardia.. Eighteen dogs were randomly assigned to sham, pacing, or pacing + Ang-(1-7) groups (n = 6 in each group). Rapid atrial pacing (500 beats/min) was maintained for 2 weeks, while the dogs in the sham group were not paced. Ang-(1-7) (6 μg/kg/h) was administered intravenously during pacing. Whole-cell patch clamp techniques were utilized to record INa from canine atrial myocytes. Reverse transcription-polymerase chain reaction was used to assess possible underlying changes in cardiac Na(+) channels (Nav1.5).. Our results showed that INa density and expression of the Nav1.5 mRNA significantly decreased following pacing (P < 0.05 vs sham); however, the half-activation voltage (V1/2act ) and half-inactivation voltage (V1/2inact ) of INa were not significantly altered (P > 0.05 vs sham). Ang-(1-7) treatment significantly increased INa densities and hyperpolarized V1/2act without concomitant changes in V1/2inact but have no effect on the expression of the Nav1.5 gene.. Ang-(1-7) significantly increased INa densities, which contributed to improving intraatrial conduction and decreasing the likelihood of atrial fibrillation maintenance.

Topics: Angiotensin I; Animals; Atrial Remodeling; Dogs; Female; Gene Expression; Male; NAV1.5 Voltage-Gated Sodium Channel; Peptide Fragments; Tachycardia, Supraventricular