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1 Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY, USA
* To whom correspondence should be addressed. E-mail: s0tyag01{at}louisville.edu.
Background/objectives: We examined the hypothesis that oxidants generated nitroso-derivatives, activated latent matrix metalloproteinase (MMP), and induced proteinase-activated receptor-1 (PAR-1), leading to disconnection between the endothelium and myocytes. Administration of cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4/CIMP) ameliorated the oxidative-proteolytic stress and endothelial-myocyte uncoupling in chronic heart failure (CHF) in mice. Methods: Aortic-venacava-fistula (AVF) was created in 30 male mice (C57BL/6J) and studied at 0, 2 and 8 wks AVF. To reverse cardiac remodeling, as measured by MMP activation, purified CIMP was administered by osmotic mini-pump subcutaneously after 8 wks AVF, and groups of mice (n=6 in each group) were examined after 12 and 16 wks. Results: Levels of PAR-1 in the left ventricle (LV) were increased at 2 and 8 wks (compared to 0 wk no CIMP treatment) but were normal at 12 and 16 wks after CIMP treatment, measured by Western blot. Similar results were obtained for the LV levels of nitrotyrosine, MMP-2, -9 activities, TIMP-1 and -3. However, the levels of TIMP-4, endothelial cell density; responses of cardiac rings to acetylcholine (ACH), and bradykinin (BK) were attenuated at 2 and 8 wks and normalized after CIMP administration in AVF mice. CIMP induced nitric oxide in microvascular endocardial endothelial cells. Conclusions: The results suggest that nitro-generation activated MMP and PAR-1, leading to endothelial-myocyte uncoupling. CIMP treatment normalized PAR-1 expression and ameliorated endothelial-myocyte uncoupling by decreasing oxidant-mediated proteolytic stress in chronic heart failure.
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