Chymase, a multifunctional mast cell serine protease, generates angiotensin (Ang) II and activates pro-matrix metalloproteinase (MMP)-2/9, in vivo, in the mouse heart. We show that combined ACE + chymase inhibition improves left ventricle (LV) function, decreases adverse cardiac remodeling, and markedly improves survival after MI (Wei et al., J Clin Invest. 120, 1229-39, 2010). However, by itself, chymase inhibition is mildly efficacious, suggesting that ACE inhibition potentiates chymase release. This is supported by the finding that ACE inhibition causes bradykinin/kinin B2 receptor-mediated release of mouse mast cell protease (MMCP)-4 (functional homolog of human chymase) in the LV interstitium in vivo. Although these findings suggest that the beneficial effects of bradykinin potentiation in the ACE-inhibitor-treated post-MI heart are counteracted by bradykinin-mediated chymase release, the downstream targets of chymase are unknown. We hypothesize that MMCP-4 release limits the cardiac efficacy of ACE inhibitor therapy in the post-MI heart because it activates pro-MMP-9 and generates Ang II. It is known that MMP-9 contributes to early post-MI LV dilatation by degrading interstitial collagen, and Ang II promotes cardiomyocyte hypertrophy and interstitial fibrosis. We will explore our hypothesis using mice with targeted deletion of MMCP-4 and/or MMP-9.
In Specific Aim 1 we will demonstrate that, after a MI, MMCP-4-dependent Ang II generation limits ACE inhibitor efficacy in reducing late-stage cardiomyocyte hypertrophy and LV interstitial fibrosis in the distal LV myocardium. Ang II binds to two receptor subtypes, AT1 and AT2. ACE-inhibited WT versus MMCP-4(-/-) mice will be treated with placebo versus a combination of AT1 + AT2 receptor blockade to confirm the hypothesis that, despite ACE inhibition, MMCP-4- dependent Ang II formation is involved in late-stage cardiomyocyte hypertrophy and LV interstitial fibrosis in the post-MI heart.
In Specific Aim 2 we will demonstrate that, in ACE inhibitor-treated mice with MI, attenuation of early LV interstitial collagen accumulation, LV dilatation and the rate of mortality are limited by MMCP-4- dependent pro-MMP-9 activation. In Part I of this Aim we will define the temporal relationship between mast cell degranulation, MMCP-4-dependent pro-MMP-2/9 activation, and LV dilatation in ACE-inhibitor treated post-MI hearts and relate these changes to early LV dilatation and dysfunction in the post-MI heart of ACE inhibitor-treated WT mice. In Part II of this Aim we will demonstrate that MMCP-4-dependent pro-MMP-9 activation limits the efficacy of ACE inhibitor therapy with respect to LV dilatation, function and survival in mice with MI. Such findings could explain why adding an AT1 receptor blocker to an ACE inhibitor does not improve survival outcomes over ACE inhibitor monotherapy. It suggests that chymase inhibition, rather than further interruption of the renin-angiotensin system, may be more efficacious in post-MI patients already treated with an ACE inhibitor. If the proposed hypotheses are confirmed, our findings would provide a foundation for the development of novel therapeutic agents directed toward patients with cardiovascular disease.
Angiotensin I-converting enzyme inhibitor therapy is particularly efficacious in improving cardiovascular survival following acute MI. We show that its efficacy, with regard to cardiac function and survival, is greatly enhanced by the addition of a chymase inhibitor. The proposed identification of the downstream targets of chymase should provide a foundation for the development of novel therapeutic agents directed toward patients with cardiovascular disease.
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