AT1 receptor antagonist therapy preferentially ameliorated right ventricular function and phenotype during the early phase of remodeling post-MI

The influence of AII on contractile dysfunction, regulation of the tyrosine kinase-dependent signaling molecule extracellular signal-regulated kinase (ERK), and natriuretic peptide gene expression were examined in the noninfarcted left ventricle (NILV) and right ventricle (RV) during the early phase of remodeling post-myocardial infarct (MI) in the rat. The selective AT1 receptor antagonist irbesartan was administered <10 h following coronary artery ligation, and rats were killed either at 4-day or 2-week post-MI. At 4 days post-MI, left ventricular systolic pressure (LVSP: sham=125±12, MI=91±4 mmHg) was decreased, whereas left ventricular end-diastolic pressure (LVEDP: sham=9±2, MI=17±2 mm Hg), right ventricular systolic (RVSP: sham=26±1, MI=34±2 mm Hg), and end-diastolic pressures (RVEDP: sham=3±0.5, MI=7±1 mm Hg) were increased. ERK phosphorylation was significantly elevated in the NILV and RV. Irbesartan (40 mg kg−1/day−1) administration did not improve left ventricular function, or suppress increased ERK phosphorylation in the 4-day post-MI rat. By contrast, irbesartan therapy normalized RVSP (MI+irbesartan=25±1 mm Hg), RVEDP (MI+irbesartan=3±0.3 mm Hg), and reduced ERK1 (MI=3.0±0.6, MI+irbesartan=2.0±0.3-fold increase), and ERK2 (MI=3.8±0.8, MI+irbesartan=2.2±0.5-fold increase) phosphorylation. In 2-week post-MI rats, biventricular dysfunction was associated with increased prepro-ANP, and prepro-BNP mRNA expression. Irbesartan therapy normalized RVSP, attenuated RVEDP, and abrogated natriuretic peptide mRNA expression (prepro-ANP; MI=9±2, MI+irbesartan=2±1-fold increase, prepro-BNP; MI=6±2, MI+irbesartan=1±1-fold increase), whereas both transcripts remained elevated in the NILV despite the partial attenuation of LVEDP. These data suggest that the therapeutic benefit of irbesartan treatment during the early phase of remodeling post-MI was associated with the preferential amelioration of RV contractile function and phenotype. Keywords: Myocardial infarct, ventricular function, AT1 receptor antagonists, cardiac remodeling Introduction It has been established that left ventricular failure is the most prevalent cause of secondary pulmonary hypertension, resulting in right ventricular dysfunction (Cody et al., 1992). A recent study has shown that right ventricular ejection fraction is an independent risk factor in patients with moderate-to-severe heart failure (Ghio et al., 2001). Clinically, the beneficial effects of angiotensin-converting enzyme (ACE) inhibitor therapy in heart failure patients have been well described (Pfeffer et al., 1992,1995; Hennekens et al., 1996). Likewise, at least in the myocardial infarct (MI) rat model, angiotensin II type 1 (AT1) receptor antagonist treatment mimicked the therapeutic effect of ACE inhibitors on left ventricular dysfunction (Smits et al., 1992; Ju et al., 1997; Richer et al., 1999). Despite these latter observations, the therapeutic benefit of either ACE inhibitors or AT1 receptor antagonists on right ventricular contractile function and remodeling post-MI remains undefined. Cardiac myocyte hypertrophy and fibroblast proliferation in the noninfarcted left ventricle (NILV) and right ventricle (RV) are predominant cellular events post-MI (Pfeffer et al., 1995). Myocyte hypertrophy is characterized by an increase in cell size and the re-expression of the fetal gene prepro-atrial natriuretic peptide (prepro-ANP), whereas uncontrolled cardiac fibroblast proliferation leads to the disproportionate synthesis and secretion of the extracellular matrix proteins collagen and fibronectin, resulting in interstitial fibrosis (Chien et al., 1991; Pfeffer et al., 1995; Weber, 1997). The prerequisite signaling events coupled to cardiac cell growth, and phenotype post-MI remains undefined, albeit several in vivo and in vitro studies have identified a potential role for the serine/threonine kinases extracellular signal-regulated kinase (ERK), and protein kinase B (PKB). The manipulation of ERK activity with transgenic mice revealed marked cardiac hypertrophy (Bueno et al., 2000, 2001). Consistent with this latter observation, ERK is recruited by several well-defined hypertrophic stimuli, including the sympathetic system, and peptide growth factors (Sadoshima & Izumo, 1993; Xiao et al., 2001). In addition, ERK activation was identified as a prerequisite event of both human and rat cardiac fibroblast proliferation (Hafizi et al., 1999; Moriguchi et al., 1999; Kim et al., 2002). In contrast to ERK, PKB represents a putative downstream target of the enzyme phosphatidylinositol 3-kinase (PI3-K), and its activation in cardiac myocytes was sufficient to induce a hypertrophic phenotype (Morisco et al., 2000; Schubert et al., 2000). In transgenic mice, PKB overexpression in cardiac myocytes caused an increase in cell size and promoted a molecular phenotype consistent with hypertrophy (Condorelli et al., 2002). Moreover, PKB represents a potent antiapoptotic molecule, and its potential activation post-MI in the NILV may act as a protective mechanism to limit cardiac myocyte apoptosis (Matsui et al., 1999). In cardiac fibroblasts, a PI3-K pathway has been implicated in cell proliferation, albeit the role of PKB in this process remains undefined (Colombo et al., 2001; Kim et al., 2002). Lastly, in ischemic or idiopathic failing human hearts, ERK, and PKB activity was increased (Haq et al., 2001). Thus, both ERK and PKB may represent early signal events required to elicit the full complement of cellular and molecular events associated with cardiac remodeling. However, the activation of either ERK or PKB, or the stimuli (e.g. hormonal or mechanical stress) implicated in their regulation in the myocardium post-MI remains undefined. The primary objective of the present study was to examine whether the early phase of remodeling post-MI in the NILV was associated with ERK and PKB recruitment, and a pattern of gene expression consistent with cardiac myocyte hypertrophy, and fibroblast proliferation. In parallel, the cellular and molecular phenotype of the RV in the post-MI rat was examined to identify whether the pattern of remodeling was similar or disparate to the NILV. Lastly, and as previously mentioned, ACE inhibitors and AT1 receptor antagonists improved ventricular function in the post-MI rat, albeit the underlying mechanisms remain equivocal. In vitro studies have demonstrated that AII can increase ERK activity in cardiac myocytes and fibroblasts, and elicit qualitatively similar molecular events characteristic of hypertrophy, and proliferation, respectively (Sadoshima & Izumo, 1993; Booz et al., 1994; Moriguchi et al., 1999). In vascular smooth muscle cells, AII treatment increased PKB activity (Takahashi et al., 1999). However, the recruitment of PKB in cardiac cells by AII remains undefined. Moreover, it remains to be demonstrated that the reported increase of local and circulating levels of AII represents an integral factor during the early phase of cardiac remodeling post-MI (Pfeffer et al., 1995). Thus, the potential role of AII in cellular and molecular remodeling, and the therapeutic effect on LV and RV contractility was assessed via the administration of the selective AT1, receptor antagonist irbesartan <10 h following coronary artery ligation.