verbatim): The PI has studied the role of the cardiac renin angiotensin system (RAS)/chymase system in mechanisms of angiotensin II (ANG II) formation in the heart in response to volume overload heart failure. These studies demonstrated increased expression of RAS and chymase in the dog heart associated with LV dilatation (decreased wall thickness/diameter ratio), increased matrix metalloproteinase (MMP) activity, and dissolution of the fine collagen weave. Neither suppression of tissue ANG II with ACE inhibitor, nor blockade of the AT1 receptor modulated this remodeling process. Further, heterozygote ACE knockout mice (1/0), having 40 percent of tissue ACE activity compared to wild type, had a significantly lower w/t diameter ratio than wild type mice in response to volume overload. There was a failure to downregulate LV MMP activity in the 1/0 mice vs. 1/1 mice and in dogs with chronic MR. In both animal models, chymase activity was upregulated and not effected by blockade of the RAS. There is recent compelling evidence that remodeling of the extracellular matrix (ECM) is regulated by MMPs in dilated cardiomyopathy. Inhibition of tissue ACE, by its effect of decreasing ANG II and increasing bradykinin (BK), can promote MMP synthesis and activation. In addition, chymase can also directly cleave and activate MMPs. Thus, the hypothesis of the current proposal is that tissue concentrations of ACE and chymase mediate the LV remodeling pattern in response to volume overload by their influence on myocardial MMP activational state. The PI will measure interstitial fluid (ISF) ANG II, BK, and MMP activational state in the conscious rat (low chymase/ACE activity ratio) and hamster (high chymase/ACE activity ratio) in response to volume overload stress. This approach combined with targeted transgenic models of variable ACE expression and increased chymase expression will relate in-vivo LV function and collagen weave by scanning EM to MMP activation. Viral vectors for chymase antisense will be utilized in the heart failure models in the rat, hamster, and mouse. In the absence of an orally effective chymase inhibitor, this approach will answer important questions regarding the physiological importance of the relative concentrations of ACE and chymase in LV remodeling in heart failure.
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