AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling
Introduction
MI induces global changes in ventricular architecture, called post-infarction LV remodeling. The process of LV remodeling involves acute phase LV dilatation due to lengthening of infarct and non-infarcted myocardium and subsequent development of myocyte hypertrophy and interstitial fibrosis in the non-infarct region. Consequently, LV function deteriorates with increasing rate of mortality (Pfeffer and Braunwald, 1990, White et al., 1987). A substantial body of evidence (Dickstein and Kjekshus, 2002, Flather et al., 2000, Pfeffer et al., 2003) has suggested that Ang II plays a critical role in post-infarction LV remodeling. Ang II has two major receptor subtypes, AT1R and AT2R, both of which are expressed in the heart (Ozono et al., 2000). It has been suggested that AT1R signaling mediates vasoconstriction, aldosterone secretion, cardiomyocyte hypertrophy, proliferation of fibroblasts, interstitial collagen deposition, and catecholamine release, all of which are implicated in the progression of LV remodeling (Harada et al., 1999). AT2R is thought to have the opposite effect to that of AT1R, and has been shown to suppress myocardial hypertrophy (Booz and Baker, 1996), fibroblast proliferation (Tsutsumi et al., 1998), and vascular cell hyperplasia (Stoll et al., 1995). We have recently demonstrated in mice that deletion of AT2R gene caused deterioration of heart failure and increased mortality during 14 days after MI (Oishi et al., 2003), suggesting that AT2R is protective against the acute phase post-infarction LV remodeling.
Recent clinical trials (Dickstein and Kjekshus, 2002, Pfeffer et al., 2003) have demonstrated that long-term administration of ARBs reduces cardiovascular mortality and morbidity effectively in patients with heart failure after MI. However, it is unclear whether ARBs may benefit the survival of patients with heart failure that frequently occurs within the first 3–4 days after the onset of infarction. Specific blockade of AT1R with ARBs results in the elevation of circulating Ang II and thus an overstimulation of AT2R (Levy, 2004, Spinale et al., 1997), indicating that the effect of ARBs could be partly mediated by its effect on AT2R. Regarding the role of AT2R, activation of AT2R does not always lead to cardioprotection, but could exert deleterious effects in certain contexts (Levy, 2004). It is therefore important to address whether ARB is beneficial in the acute phase after MI, and whether the effects of ARBs are brought about by blockade of AT1R or by stimulation of AT2R. Of note, a relative abundance of AT2R to AT1R in the heart is highest in humans compared to rodents and other animal models (Tsutsumi et al., 1998, Wharton et al., 1998).
In the present study using mice lacking AT2R, we investigated the effects of valsartan on LV remodeling, focusing on the LV dilatation and development of heart failure in the acute phase after MI. By comparing the effect of valsartan between wild-type and the knockout mice, we can determine the contribution of AT2R.
Section snippets
Animals
Adult male AT2R-knockout mice (Agtr2−)(Akishita et al., 2000, Hein et al., 1995, Oishi et al., 2003) and wild-type mice (Agtr2+) littermates were used in this study. These mice were back-crossed for at least 6 generations onto a FVB/N background (Akishita et al., 2000, Hein et al., 1995). All experimental procedures were approved and carried out in accordance with the Guidelines of Hiroshima University Graduate School of Biomedical Sciences.
Experimental protocols
Myocardial infarction was induced as previously
Survival rate after myocardial infarction
Consistent with our previous observation (Oishi et al., 2003), the survival rate of Agtr2− mice treated with a vehicle (33%) was lower than that of Agtr2+ mice treated with a vehicle (41%), although the difference did not reach statistical significance. Valsartan treatment improved the survival rates of both strains of mice (61% for Agtr2+ mice and 53% for Agtr2− mice).
Hemodynamic and physiological assessments
There was no difference between BPs and HRs in the two strains of mice on day 0 (Table 1). Treatment with valsartan or a
Discussion
LV remodeling after MI is a complex process consisting of acute phase infarct expansion and subsequent myocyte hypertrophy and interstitial fibrosis in the residual myocardium, all of which lead to LV dysfunction. In the present study, effects of valsartan on LV remodeling during the first 2 weeks after MI were examined in Agtr2+ and Agtr2− mice. Valsartan effectively inhibited cardiomyocyte hypertrophy, LV dilatation, and pulmonary congestion, thereby improving survival rate. On the other
Acknowledgements
Funding Source: This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Japan(17590493) and grants from Kurozumi Medical Foundation and Takeda Science Foundation.
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