Cartilage Oligomeric Matrix Protein: Matricellular and Matricrine Signaling in Cardiovascular Homeostasis and Disease

Abstract

Cardiovascular (CV) diseases remain a leading cause of morbidity and mortality in the world. Increasing the understanding of the pathogenesis of various CV diseases may provide novel therapeutic targets to improve their prevention and treatment. Cartilage oligomeric matrix protein (COMP), also known as thrombospondin-5 (TSP-5), is a matricellular protein that is abundantly expressed in both cartilage and the CV system. Our group and others have identified COMP as playing critical roles in maintaining CV homeostasis. COMP, expressed and produced by vascular smooth muscle cells (VSMCs), maintains VSMC contractile phenotypes. COMP deficiency enhances VSMC migration and aggravates VSMC calcification and atherosclerosis. Moreover, a lack of COMP leads to spontaneous dilated cardiomyopathy in mice. COMP is also secreted by platelets in circulating blood and negatively regulates haemostasis and thrombosis. A series of COMP binding proteins, such as integrin α7β1, integrin β3, thrombin, and bone morphogenetic protein 2, have been identified in the CV system, and they have been determined to mediate various COMP functions. The matrix metalloproteinase (A Disintegrin and Metalloproteinase with Thrombospondin motifs) ADAMTS-7 is a regulatory enzyme that is responsible for the degradation of COMP in the CV system. ADAMTS-7 expression correlates with atherosclerosis and vascular calcification in both human genome-wide association studies and in vivo mice models via COMP-dependent and COMP-independent mechanisms. In this review, we summarize what is currently known about the matricellular and matricrine signaling of COMP mediated by its respective binding partners as well as its proteolytic regulation by ADAMTS-7 in CV disease.

Keywords: ADAMTS-7; COMP; atherosclerosis; calcification; dilated cardiomyopathy; interactome; restenosis; thrombosis.