Role of various proteases in cardiac remodeling and progression of heart failure

Abstract

It is believed that cardiac remodeling due to geometric and structural changes is a major mechanism for the progression of heart failure in different pathologies including hypertension, hypertrophic cardiomyopathy, dilated cardiomyopathy, diabetic cardiomyopathy, and myocardial infarction. Increases in the activities of proteolytic enzymes such as matrix metalloproteinases, calpains, cathepsins, and caspases contribute to the process of cardiac remodeling. In addition to modifying the extracellular matrix, both matrix metalloproteinases and cathepsins have been shown to affect the activities of subcellular organelles in cardiomyocytes. The activation of calpains and caspases has been identified to induce subcellular remodeling in failing hearts. Proteolytic activities associated with different proteins including caspases, calpain, and the ubiquitin-proteasome system have been shown to be involved in cardiomyocyte apoptosis, which is an integral part of cardiac remodeling. This article discusses and compares how the activities of various proteases are involved in different cardiac abnormalities with respect to alterations in apoptotic pathways, cardiac remodeling, and cardiac dysfunction. An imbalance appears to occur between the activities of some proteases and their endogenous inhibitors in various types of hypertrophied and failing hearts, and this is likely to further accentuate subcellular remodeling and cardiac dysfunction. The importance of inhibiting the activities of both extracellular and intracellular proteases specific to distinct etiologies, in attenuating cardiac remodeling and apoptosis as well as biochemical changes of subcellular organelles, in heart failure has been emphasized. It is suggested that combination therapy to inhibit different proteases may prove useful for the treatment of heart failure.

Role for Cysteine Protease Cathepsins in Heart Disease

“…The roles of proteolytic enzymes in various cardiovascular diseases have been covered by recent comprehensive reviews. 1,2 Next, we consider the role of cathepsins in CCVD in greater detail. The sections below describe the cathepsins involved in several myocardial, coronary, and valve diseases, especially with respect to their potential application as diagnostic and/or prognostic markers and drug targets to prevent CCVD.…”

“…Dysregulation of proteolytic enzymes may disrupt these normal biological processes in myocardium-coronary-valve disease (CCVD). Substantial evidence supports the involvement of matrix metalloproteinase (MMP) and serine protease families in this process (reviewed elsewhere 1,2 ). Cysteinyl proteases have received much less consideration in this regard, even though cardiovascular cells and macrophages with greatly expanded lysosomal compartments figure prominently in the pathogenesis of CCVD.…”

Role of intracellular Ca2+ overload in inducing changes in cardiac gene expression

“…Varying degrees of alterations in functional and biochemical activities of SL, SR and MF activities have also been shown to occur in CP hearts as a consequence of intracellular Ca 2+ overload (13)(14)(15)17,(21)(22)(23). Although elevated levels of intracellular Ca 2+ have been observed to activate proteases, such as calpains, directly the observed increase in mRNA levels for both calpain-1 and -2 proteins may also contribute to increased calpain activity in hearts under different pathological conditions associated with the occurrence of intracellular Ca 2+ overload (27)(28)(29)(30)(31). Thus, it appears that the observed depressions in SL, SR and MF gene expression, as well as the increased gene expression for calpains due to intracellular Ca 2+ overload, may account for remodelling of subcellular organelles observed in the hearts subjected to CP.…”

“…In the present study, we examined whether hearts perfused with Ca 2+ -free medium followed by reperfusion with medium containing different concentrations of Ca 2+ exhibit alterations in gene expression for SL Na + -K + ATPase and Na + -Ca 2+ exchanger, SR Ca 2+ -pump ATPase, Ca 2+ -release channel and phospholamban (PLB), as well as MF α-and β-myosin heavy chain proteins. Because subcellular remodelling in the failing heart is dependent on the balance between changes in gene expression and activities of proteolytic enzymes, such as calpain (27)(28)(29)(30)(31)(32)(33), messenger RNA (mRNA) levels for both calpain-1 and calpain-2 were measured in CP hearts. It may be noted that subcellular remodelling in failing hearts has also been suggested to be the result of activation of different proteolytic enzymes (27,28).…”

Mitochondrial Transcription Factor A's role in heart failure.

“…An imbalance of proteases and their inhibitors is present within the heart failure model (Müller and Dhalla 2012;Wei et al 2012). Alterations in cytoskeletal and contractile proteins due to calpain protease up-regulation causes the degradation of proteins such as myosin, F-actin, and titin, resulting in a disorganized sarcomere (Ellis et al 2010).…”