Published Online
on April 26, 2004

A more recent version of this article appeared on May 4, 2004

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Submitted on February 3, 2003
Revised on January 20, 2004
Accepted on January 22, 2004

Attenuation of Oxidative Stress and Remodeling by Cardiac Inhibitor of Metalloproteinase Protein Transfer

Michael J. Cox MD, Urseline A. Hawkins MD, Brian D. Hoit MD, and Suresh C. Tyagi PhD^*

From the Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, Ky (M.J.C., U.A.H., S.C.T.); and Department of Medicine, Division of Cardiology, Case Western Reserve University, Cleveland, Ohio (B.D.H.).

^* To whom correspondence should be addressed. E-mail: s0tyag01{at}louisville.edu.

Background--Matrix metalloproteinase (MMP) and cardiac inhibitor of metalloproteinase (CIMP) are coexpressed in the heart. Although it is known that oxidative stress activates MMP and CIMP inhibits MMP, it is unclear whether CIMP administration attenuates oxidative stress and MMP-mediated cardiac dilatation.

Methods and Results--Arteriovenous fistula (AVF) was created in C57BL/J6 mice, and CIMP was administered to AVF and sham mice by protein transfer into peritoneal cavity by minipump for 4 weeks. Mice were grouped as follows: sham; sham+CIMP; AVF; and AVF+CIMP (n=6). In vivo left ventricular (LV) pressure was measured. Plasma and LV tissue levels of CIMP were measured by Western analysis. LV levels of NADPH oxidase activity, marker of oxidative stress, were increased in AVF mice and decreased in AVF mice treated with CIMP. Compared with sham, CIMP was decreased in AVF mice, and CIMP protein transfer increased plasma and LV tissue levels of CIMP in AVF mice; there was no increase in sham animals. In situ zymography demonstrated a robust increase in MMP activity in the hearts from AVF mice compared with sham, and treatment with CIMP decreased MMP activity. In AVF mice, the cardiac pressure-length relationship was similar to that observed in sham mice after administration of CIMP. Contractile responses of normal LV rings were measured in the presence and absence of CIMP. CIMP shifted the pressure-length relationship to the left, attenuated LV dilatation, and had no effect on CaCl₂-mediated contraction.

Conclusions--Treatment of AVF mice with CIMP significantly abrogated the contractile dysfunction and decreased the oxidative stress in volume overload-induced heart failure.

Key words: proteomics • nitric oxide • NADPH oxidase • relaxation • heart failure

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