Protease-activated receptor and endothelial-myocyte uncoupling in chronic heart failure

• Published in: American journal of physiology. Heart and circulatory physiology 2005-06, Vol.288 (6), p.H2770-H2777
• Main Authors: Moshal, Karni S, Tyagi, Neetu, Henderson, Brooke, Ovechkin, Alexander V, Tyagi, Suresh C
• Format: Article
• Language: English
• Subjects: Animals; Arteriovenous Fistula - physiopathology; Disease Models, Animal; Endothelium, Vascular - physiopathology; Heart Failure - physiopathology; Male; Mice; Mice, Inbred C57BL; Muscle Cells - physiology; Receptor, PAR-1 - physiology; Ventricular Function, Left
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01146.2004

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky Submitted 15 November 2004 ; accepted in final form 26 January 2005 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. proteomics; shedding; nitric oxide; NADPH oxidase; cardiac ring; contraction; relaxation; dilatation; matrix metalloproteinase; nitrotyrosine; tissue inhibitors of metalloproteinase; coupling Address for reprint requests and other correspondence: S. C. Tyagi, Univ. of Louisville School of Medicine, A-1115, Dept. of Physiology and Biophysics, 500 S. Preston St., Louisville, KY 40202 (E-mail: s0tyag01{at}louisville.edu )