Calpain inhibition preserves myocardial structure and function following myocardial infarction

Abstract

Mani SK, Balasubramanian S, Zavadzkas JA, Jeffords LB, Rivers WT, Zile MR, Mukherjee R, Spinale FG, Kuppuswamy D. Calpain inhibition preserves myocardial structure and function following myocardial infarction. Am J Physiol Heart Circ Physiol 297: H1744 -H1751, 2009. First published September 4, 2009 doi:10.1152/ajpheart.00338.2009.-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 2ϩ -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 ϭ 6) and untreated (n ϭ 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 Ϯ 2% pre-MI to 30 Ϯ 4% with MI only vs. 41 Ϯ 2% with MI ϩ calpeptin] and attenuated the increase in EDV [EDV increased from 42 Ϯ 2 l pre-MI to 73 Ϯ 4 l with MI only vs. 55 Ϯ 4 l with MI ϩ 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 SEVERAL CARDIOVASCULAR PATHOLOGIES, including myocardial infarction (MI), are associated with left ventricular (LV) remodeling as defined by changes in LV geometry and structure, and concomitantly, LV pump function can be adversely affected post-MI (7,34,46). At the cellular level, both qualitative and quantitative changes in cardiomyocytes can also contribute to both compromised contractile function (9) and programmed cell death (21,22,30). One common mechanism for this maladaptive remodeling at the cardiomyocyte level is hyperactivation of cellular endopeptidases, such as members of the calpain (6, 15, 16, 58) and caspase families (5,22,26,54). Activation of these proteases may result in the cleavage of several key cellular proteins that result in the loss of contractile proteins and thus function of cardiac muscle cells.Although studies demonstrate activation of both calpain and caspases with cardiac disease states, our laboratory (30) recently demonstrated that calpain activation contributes substantially to programmed cell death in pressure-overloaded (PO) feline myocardium. Calpains are a family of Ca 2ϩ -dependent cysteine proteases. The predominant ...

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

“…Calpain activity is increased in the infarcted heart and in myocardia of patients with heart failure (9,10). Pharmacologic inhibition of calpain reduces ischemic cardiac injury and preserves cardiac structure after acute MI (11)(12)(13)(14). A recent study showed that calpain-1 knock-out reduced whereas calpain-1 overexpression enhanced myocardial injury and dysfunction within 4 days after coronary occlusion (15).…”

Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks

“…These findings suggest that calpain-inhibition may still be a potentially useful therapeutic approach. Thus over-expression of calpastatin or use of exogenous calpain inhibitors has been shown to ameliorate or reduce: a) sepsisinduced muscle (diaphragm 122 and heart 123 ) weakness, b) post-MI cardiac muscle remodeling 124 , c) disuse atrophy 125 , and d) hyperglycemia-related cardiac muscle dysfunction 126 .…”

Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats’ hearts

“…At first it is beneficial, leading to continuing reduction of cardiac function and finally, after days and weeks, it causes heart failure (HF) [4,5]. Owing to the quantitative and qualitative changes in cardiomyocytes, LV contractile function is impaired after MI [6]. Many studies have shown that apoptosis (programmed cell death) of cardiomyocytes is one of the mechanisms leading to ventricular remodelling in animal models and human disease [5,7,8].…”

“…One common mechanism of remodelling is hyper activation of caspase families. Activation of these proteases may cause disintegration of various key cellular proteins, thereby resulting in the loss of contractile proteins and hence reduction of cardiac muscle cell function [6].…”