Impairment of Cardiac Function and Remodeling Induced by Myocardial Infarction in Rats are Attenuated by the Nonpeptide Angiotensin-(1-7) Analog AVE 0991

Aims: We evaluated effects of the nonpeptide angiotensin (ANG)-(17) analog AVE 0991 (AVE) on cardiac function and remodeling as well as transforming growth factor-beta1 (TGF-beta 1)/tumor necrosis factor-alpha (TNF-a) expression in myocardial infarction rat models. Methods and Results: SpragueDawley rats underwent either sham surgery or coronary ligation. They were divided into four groups: sham, control, AVE, and AVE+A-779 [[D-Ala7]-ANG-(17), a selective antagonist for the ANG-(17)] group. After 4 weeks of treatment, the AVE group displayed a significant elevation in left ventricular fractional shorting (LVFS) (25.5 +/- 7.3% vs. 18.4 +/- 3.3%, P < 0.05) and left ventricular ejection fraction (LVEF) (44.8 +/- 7.6% vs. 32.7 +/- 6.5%, P < 0.05) when compared to the control group, but no effects on the left ventricular end-diastolic and end-systolic diameters (LVDd and LVDs, respectively) were observed. In addition, we found that the myocyte diameter (18 +/- 2 mu m vs. 22 +/- 4 mu m, P < 0.05), infarct size (42.6 +/- 3.6% vs. 50.9 +/- 4.4%, P < 0.001) and collagen volume fraction (CVF) (16.4 +/- 2.2% vs. 25.3 +/- 3.2%, P < 0.001) were significantly reduced in the AVE group when compared to the control group. There were no differences in LVFS, LVEF, myocyte diameter, and infarct size between the control and AVE+A-779 groups. AVE also markedly attenuated the increased mRNA expression of collagen I (P < 0.001) and collagen III (P < 0.001) and inhibited the overexpression of TGF-beta 1 (P < 0.05) and TNF-a (P < 0.05) compared to the control group. Conclusion: AVE could improve cardiac function and attenuate ventricular remodeling in MI rat models. It may involve the inhibition of inflammatory factors TGF-beta 1/TNF-a overexpression and the action on the specific receptor Mas of ANG-(17).