Calpain inhibition preserves myocardial structure and function following myocardial infarction

1 Division of Cardiology, Department of Medicine, 2 Division of Cardiothoracic Surgery, Department of Surgery, and the 3 Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina Submitted April 7, 2009 ; accepted in final form September 1, 2009 Cardiac pathology, such as myocardial infarction (MI), activates intracellular proteases that often trigger programmed cell death and contribute to maladaptive changes in myocardial structure and function. To test whether inhibition of calpain, a Ca 2+ -dependent cysteine protease, would prevent these changes, we used a mouse MI model. Calpeptin, an aldehydic inhibitor of calpain, was intravenously administered at 0.5 mg/kg body wt before MI induction and then at the same dose subcutaneously once per day. Both calpeptin-treated ( n = 6) and untreated ( n = 6) MI mice were used to study changes in myocardial structure and function after 4 days of MI, where end-diastolic volume (EDV) and left ventricular ejection fraction (EF) were measured by echocardiography. Calpain activation and programmed cell death were measured by immunohistochemistry, Western blotting, and TdT-mediated dUTP nick-end labeling (TUNEL). In MI mice, calpeptin treatment resulted in a significant improvement in EF [EF decreased from 67 ± 2% pre-MI to 30 ± 4% with MI only vs. 41 ± 2% with MI + calpeptin] and attenuated the increase in EDV [EDV increased from 42 ± 2 µl pre-MI to 73 ± 4 µl with MI only vs. 55 ± 4 µl with MI + calpeptin]. Furthermore, calpeptin treatment resulted in marked reduction in calpain- and caspase-3-associated changes and TUNEL staining. These studies indicate that calpain contributes to MI-induced alterations in myocardial structure and function and that it could be a potential therapeutic target in treating MI patients. cardiomyocytes; cell death Address for reprint requests and other correspondence: D. Kuppuswamy, Gazes Cardiac Research Institute, 114 Doughty St., Charleston, SC 29425-2221 (e-mail: kuppusd{at}musc.edu ).