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BASIC SCIENCE

Long-Term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction

^* Division of Cardiology, VA Medical Center and University of Minnesota, Minneapolis, Minnesota, USA

Manuscript received June 19, 2003; revised manuscript received September 15, 2003, accepted September 15, 2003.

^* Reprint requests and correspondence: Dr. Y. Chandrashekhar, Associate Professor of Medicine, University of Minnesota, Division of Cardiology IIIc, VAMC, 1 Veterans Drive, Minneapolis, Minnesota 55417, USA.
shekh003{at}tc.umn.edu

OBJECTIVES: This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling.

BACKGROUND: Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction.

METHODS: A 28-day infusion of caspase inhibitor (n = 12) or vehicle (n = 9) was administered to rats immediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry.

RESULTS: Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to-body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI.

CONCLUSIONS: Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling. These findings may have important therapeutic implications in post-MI HF.

Abbreviations and Acronyms   ANOVA = analysis of variance   DMSO = dimethyl sulfoxide   HF = heart failure   LV = left ventricle/ventricular   MI = myocardial infarction

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