Protease-activated receptor and endothelial-myocyte uncoupling in chronic heart failure.
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. Aortic-vena cava fistula (AVF) was created in 30 male mice (C57BL/6J) and studied at 0-, 2-, and 8-wk AVF. To reverse cardiac remodeling, as measured by MMP activation, purified CIMP was administered by an osmotic minipump subcutaneously after 8-wk AVF, and groups of mice (n = 6 mice/group) were examined after 12 and 16 wk. Levels of PAR-1 in the left ventricle (LV) were increased at 2 and 8 wk (compared with 0 wk of no CIMP treatment) but were normal at 12 and 16 wk after CIMP treatment, as measured by Western blot analysis. Similar results were obtained for LV levels of nitrotyrosine, MMP-2 and -9 activities, and TIMP-1 and -3. However, the levels of TIMP-4, endothelial cell density, and responses of cardiac rings to acetylcholine and bradykinin were attenuated at 2 and 8 wk and normalized after CIMP administration in AVF mice. CIMP induced nitric oxide in microvascular endocardial endothelial cells. 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 CHF.
Moshal
Karni S
KS
Univ. of Louisville School of Medicine, A-1115, Dept. of Physiology and Biophysics, 500 S. Preston St., Louisville, KY 40202, USA.
Tyagi
Neetu
N
Henderson
Brooke
B
Ovechkin
Alexander V
AV
Tyagi
Suresh C
SC
D000818:Animals; D001164:Arteriovenous Fistula / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000502:physiology*; D016277:Ventricular Function, Left
D044463:Receptor, PAR-1