Role of Protease Activation in Subcellular Remodeling and Heart Failure

Abstract

Both intracellular and extracellular proteases including matrix metalloprotease (MMP2 and MMP9) and calpains are well known to play a critical role in the development of cardiac remodeling and heart failure due to hypertension, valvular disorders, myocardial infarction, and dilated cardiomyopathies. These proteolytic enzymes are considered to be activated due to the elevated levels of plasma hormones including angiotensin II, catecholamines, endothelin, vasopressin, and serotonin. The activation of these proteases has been shown to produce marked changes in the composition and structure of the extracellular matrix as well as sarcolemma, sarcoplasmic reticulum, myofibrils, and mitochondria. Such alterations in the function of the extracellular matrix and subcellular organelles due to the activation of different proteases appear to occur as a consequence of oxidative stress and intracellular Ca2+-overload, which are considered to result in cardiac dysfunction in the failing heart. The activation of different proteases in the failing hearts also seems to be dependent upon changes in the activities and contents of their endogenous inhibitors such as tissue inhibitors of matrix metalloproteases and calpastatins. It is becoming evident that alterations in the activation of both intracellular and extracellular proteases as well as changes in their endogenous inhibitors depend upon the stage and type of heart failure. Thus, a great deal of attention needs to be paid towards the prevention of protease activation and subcellular remodeling for improving the treatment of cardiac dysfunction in heart failure.