Role of proteases in the pathophysiology of cardiac disease

Abstract

Cardiovascular disease is a major cause of death and thus a great deal of effort has been made in salvaging the diseased myocardium. Although various factors have been identified as possible causes of different cardiac diseases such as heart failure and ischemic heart disease, there is a real need to elucidate their role for the better understanding of the cardiac disease pathology and formulation of strategies for developing newer therapeutic interventions. In view of the intimate involvement of different types of proteases in maintaining cellular structure, the role of proteases in various cardiac diseases has become the focus of recent research. Proteases are present in the cytosol as well as are localized in a number of subcellular organelles in the cell. These are known to use extracellular matrix, cytoskeletal, sarcolemmal, sarcoplasmic reticular, mitochondrial and myofibrillar proteins as substrates. Work from different laboratories using a wide variety of techniques has shown that the activation of proteases causes alterations of a number of specific proteins leading to subcellular remodeling and cardiac dysfunction. Inhibition of protease action by different drugs and agents, therefore, has a clinical relevance and is expected to form a part of new treatment paradigm for improving heart function. This review examines the biochemistry and localization of some of the proteases in the cardiac tissue in addition to identification of the sites of action of some protease inhibitors.

Calpain inhibition preserves myocardial structure and function following myocardial infarction

“…The cleavage of intracellular target proteins by calpain may contribute to both programmed cell death and contractile dysfunction as part of pathological remodeling. In the heart, numerous studies have indicated that increased calpain activity might be a contributing factor to various pathological states, including MI, hypertensive cardiomyopathy, and ischemia-reperfusion injury (1,23,24,37,39,44,47). In the case of MI, the levels of both -and m-calpain isoforms were shown to increase in rats following left ventricular coronary artery ligation for 2 wk, and cardiac failure then developed by 8 wk (47) with profound cardiac remodeling and concomitant calpain activity.…”

“…Calpain activation results in the cleavage of a number of specific cardiomyocyte proteins that might lead to subcellular remodeling and contractile dysfunction (44). Calpain-mediated proteolysis of contractile proteins, such as troponins, has been demonstrated in stunned myocardium (17).…”

Effects of Age on Plasma Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs)

“…This study will focus on one potential pathophysiologic mechanism of LV remodeling, changes in extracellular matrix (ECM) regulatory proteases. The matrix metalloproteinases (MMPs), and their tissue inhibitors, the TIMPs, constitute one important proteolytic pathway which can affect remodeling of the left ventricle by altering cardiomyocyte and/or ECM structure and composition (9)(10)(11)(12)(13). MMPs degrade fibrillar proteins, activate biologically important molecules, and modulate ECM remodeling (9,10,(12)(13)(14)(15)(16)(17)(18)(19).…”

Calpain Expression and Activity during Lens Fiber Cell Differentiation

“…In vivo, calpains are believed to function in myoblast fusion (12), long term potentiation (13), and cellular mobility (14). Unregulated calpain activity, secondary to intracellular calcium overload, is associated with several pathological conditions, including Alzheimer disease (15), animal models of cataract (16), myocardial (17), and cerebral ischemia (18).…”