Isoproterenol-induced impairment of heart function and remodeling are attenuated by the nonpeptide angiotensin-(1-7) analogue AVE 0991
Introduction
Cardiac remodeling is a pathological condition frequently associated to afterload-induced heart hypertrophy or myocardial infarction. In these conditions the activation of the renin–angiotensin system (RAS) plays a crucial role in the progression of the disease. Angiotensin (Ang) II contributes to cardiac remodeling after myocardial infarction by stimulating myocyte hypertrophy and myofibroblast proliferation. Conversely, Ang-(1-7) has well-established beneficial effects on cardiac function (Ferreira et al., 2001, Ferreira et al., 2002, Loot et al., 2002) and has been also described as an antifibrotic and antitrophic peptide. Ang-(1-7) reduces the growth of cardiomyocytes (Tallant et al., 2005) acting through the GPCR (G-protein coupled receptor) Mas (Santos et al., 2003) and has an inhibitory effect on collagen synthesis (Iwata et al., 2005). Recently, we have found that hearts from Mas-deficient mice exhibited a marked change in extracellular matrix protein expression to a pro-fibrotic profile accompanied by an important cardiac dysfunction (Castro et al., 2006, Santos et al., 2006). Moreover, Grobe et al., 2006, Grobe et al., 2007 reported that Ang-(1-7) prevents cardiac fibrosis elicited by either DOCA-salt treatment or Ang II infusion independent of blood pressure changes. Transgenic rats TGR(A1-7)3292, which have a 2.5-fold increase in plasma Ang-(1-7) levels, present a less pronounced cardiac hypertrophy induced by isoproterenol, a slight but significant increase in dP/dt, a reduced duration of reperfusion arrhythmias, and an improved post-ischemic function in isolated perfused hearts (Santos et al., 2004).
Recently, Wiemer et al. (2002) described a nonpeptide compound AVE 0991 which mimics the effects of Ang-(1-7) on the endothelium. It was observed that AVE 0991 evoked a similar nitric oxide/superoxide release profile to that observed with Ang-(1-7). Other studies have demonstrated that AVE 0991 acts as a Mas agonist in the kidney (Pinheiro et al., 2004) and blood vessels (Faria-Silva et al., 2005, Lemos et al., 2005) and functions similarly to Ang-(1-7) in the heart (Benter et al., 2006, Ferreira et al., 2007). The cardioprotective effects of AVE 0991 were qualitatively comparable to those of Ang-(1-7), i.e. improvement of the post-ischemic contractile function in isolated perfused hearts from spontaneously hypertensive rats (SHR) treated with l-NAME (Benter et al., 2006) and decrease of the infarcted area induced by left coronary artery ligation (Ferreira et al., 2007).
The current study was designed to evaluate the effects of AVE 0991 on cardiac remodeling using a model of heart dysfunction induced by isoproterenol. In addition, we studied the effects of AVE 0991 on cardiac function in this model.
Section snippets
Animals
Male Wistar rats weighting 250 to 300 g were used in this study. All rats were provided by the animal facilities of the Biological Sciences Institute (CEBIO, Federal University of Minas Gerais). All animal procedures were performed in accordance with institutional guidelines approved by local authorities.
Experimental protocols
Heart dysfunction was induced by daily injection of isoproterenol (2 mg/kg i.p. diluted in 0.9% NaCl) during 7 days. The rats were divided into four groups: control (0.9% NaCl i.p. plus water
Results
As shown in Table 1, isoproterenol treatment induced a significantly cardiac hypertrophy when expressed as the ratio of heart weight/body weight (5.38 ± 0.12 vs. 4.53 ± 0.22 mg/g in vehicle-treated rats, p < 0.05). This effect was mainly due to the hypertrophy of left ventricle tissue (3.08 ± 0.06 vs. 2.50 ± 0.05 mg/g in vehicle-treated rats, p < 0.05) since no significant differences in tissue weight/body weight ratios were observed in right ventricle or atria. AVE 0991 completely blocked the hypertrophy
Discussion
The nonpeptide Ang-(1-7) analogue, AVE 0991, is a synthetic compound capable of mimicking the effects of Ang-(1-7), at least in vessels (Wiemer et al., 2002, Faria-Silva et al., 2005, Lemos et al., 2005), kidney (Pinheiro et al., 2004), and heart (Benter et al., 2006, Ferreira et al., 2007). In a previous study, we found that AVE 0991 treatment during 7 days significantly improved myocardial function and decreased the infarcted area induced by left coronary artery ligation (Ferreira et al., 2007
Acknowledgments
The authors thank Dr. Jurgen Punter from Sanofi-Aventis for kindly providing AVE 0991. This work was supported in part by PRPq (Pró-reitoria de pesquisa — UFMG), PROGRAD-PAD (Pró-reitoria de graduação — UFMG), CNPq-PRONEX (Conselho Nacional de Desenvolvimento Científico e Tecnológico), FAPEMIG-PRONEX (Fundação de Amparo à Pesquisa de Minas Gerais). The Zeiss confocal microscope is located in the Centro de Microscopia (CEMEL), Instituto de Ciências Biológicas, Universidade Federal de Minas
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Anderson J. Ferreira and Thauana L. Oliveira contributed equally to this work.