Elsevier

Life Sciences

Volume 81, Issue 11, 23 August 2007, Pages 916-923
Life Sciences

Isoproterenol-induced impairment of heart function and remodeling are attenuated by the nonpeptide angiotensin-(1-7) analogue AVE 0991

https://doi.org/10.1016/j.lfs.2007.07.022Get rights and content

Abstract

The aim of this study was to evaluate the effects of AVE 0991 (AVE), a nonpeptide compound that mimics Ang-(1-7) actions, on cardiac remodeling. Heart hypertrophy and heart dysfunction were induced by isoproterenol (ISO) (2 mg/kg i.p./day for 7 days) in male Wistar rats. At the end of the 7-day period, the hearts were perfused according to the Langendorff method to evaluate cardiac function. The hearts, atria, and right and left ventricles wet weights were recorded, normalized for body weight and then expressed as muscle mass index (mg/g). In addition, serial sections from left ventricle were stained with hematoxylin–eosin for cell morphometry and with collagen-specific Masson's trichrome for detection of fibrosis. Immunofluorescence-labeling and confocal microscopy were used to investigate the distribution and deposition of collagen types I, III, VI, and fibronectin. AVE reduced the ISO-induced hypertrophy as quantified by myocyte diameter measurements (Control: 10.60 ± 0.08 μm; ISO: 14.60 ± 0.11 μm; ISO + AVE: 11.22 ± 0.08 μm, n = 5). In addition, AVE markedly attenuated the increase of extracellular matrix proteins induced by ISO. AVE treatment also attenuated the decrease in systolic tension and ± dT/dt and exacerbated the vasodilatation induced by ISO. These results show that AVE has a cardioprotective effect on ISO-induced cardiac remodeling.

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

References (31)

  • FerreiraA.J. et al.

    The nonpeptide angiotensin-(1-7) receptor Mas agonist AVE 0991 attenuates heart failure induced by myocardial infarction

    American Journal of Physiology

    (2007)
  • FerreiraA.J. et al.

    Angiotensin-(1-7): cardioprotective effect in myocardial ischemia/reperfusion

    Hypertension

    (2001)
  • FerreiraA.J. et al.

    Angiotensin-(1-7) improves the post-ischemic function in isolated perfused rat hearts

    Brazilian Journal of Medical and Biological Research

    (2002)
  • FreundC. et al.

    Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo

    Circulation

    (2005)
  • GoulterA.B. et al.

    ACE2 gene expression is up-regulated in the human failing heart

    BMC Medicine

    (2004)
  • Cited by (55)

    • AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress

      2016, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      Several studies demonstrated that ANG-(1-7) has antihypertrophic and antifibrotic functions. AVE 0991 is the agonist of Ang-(1-7)'s receptor, previous evidence showed that AVE 0991 attenuated cardiac remodeling in renovascular hypertensive rats [8,11]. The present study suggested that AVE 0991 treatment decreased cardiac hypertrophy induced by aortic banding and improved heart function.

    • ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis

      2016, Pharmacological Research
      Citation Excerpt :

      Both compounds have high specificity for the Mas receptor [103⿿106]. As previously mentioned, many studies have shown beneficial effects of AVE0991 in animal models of hypertension, cardiovascular and renal diseases [20,21,106⿿109]. Clinically, one important advantage of AVE0991 is that it is a more stable compound in regard to oral administration and greater half-life as compared to Ang-(1⿿7) [103].

    • Mas Agonists

      2015, The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications
    • The nonpeptide ANG-(1-7) mimic AVE 0991 attenuates cardiac remodeling and improves baroreflex sensitivity in renovascular hypertensive rats

      2013, Life Sciences
      Citation Excerpt :

      The discovery of AVE 0991 (Wiemer et al., 2002) as a biologically active compound, resistant to gastric enzymes and showing effects similar to those of Ang-(1–7), made it possible to explore the role of Ang-(1–7) in different pathologies such as cardiovascular diseases. Studies on normotensive animals have shown that short-term treatment with AVE 0991 (1 mg/kg; for 7 or 4 weeks) did not change baseline BP and HR in rats subjected to isoproterenol-induced cardiac hypertrophy and dysfunction (Ferreira et al., 2007a) or in rats that underwent left coronary ligation (Zeng et al., 2012). In keeping with these observations, our present results showed that treatment with AVE 0991 1 or 3 mg/kg did not alter the baseline BP in normotensive SHAM rats.

    View all citing articles on Scopus
    1

    Anderson J. Ferreira and Thauana L. Oliveira contributed equally to this work.

    View full text