Elucidation of the role of canstatin, a proteolytic fragment of extracellular matrix, in cardiac diseases

Abstract

Extracellular matrix (ECM) is a group of macromolecules contributing to support tissue structure and maintain homeostasis. Accumulating evidence suggest that ECM-degrading enzymes contribute to cause cardiac remodeling through the proteolytic degradation of ECM during cardiac diseases. Although several mechanisms have been proposed, relationships between the ECM degradation and development of cardiac diseases have not been fully clarified. In order to explore them, our group focused on matricryptin, a group of bioactive fragments cleaved from ECM. Type IV collagen, a major component of basement membrane, is ubiquitously expressed around cardiac cells. We showed that canstatin, a cleaved fragment of type IV collagen α2 chain, is abundantly expressed in normal myocardial tissue, while it decreases in the infarcted area of myocardial infarction model rats. Canstatin has been previously investigated as an endogenous anti-angiogenic and anti-tumor factor. However, the roles of canstatin in cardiac cells have not been elucidated. We for the first time showed that canstatin exerts cytoprotective effects against hypoxia-induced cell death in H9c2 cardiomyoblasts. Canstatin also mediates the biologic functions such as proliferation and migration in cardiac fibroblasts from normal rats and in myofibroblasts from myocardial infarction model rats. These findings provide a new insight into the role of canstatin in cardiac remodeling, which can contribute to develop new drugs for cardiac diseases.