Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification

Rationale: Intimal calcification is highly correlated with atherosclerotic plaque burden, but the underlying mechanism is poorly understood. We recently reported that cartilage oligomeric matrix protein (COMP), a component of vascular extracellular matrix, is an endogenous inhibitor of vascular smooth muscle cell calcification. Objective: To investigate whether COMP affects atherosclerotic calcification. Methods and Results: ApoE(-/-)COMP(-/-) mice fed with chow diet for 12 months manifested more extensive atherosclerotic calcification in the innominate arteries than did ApoE(-/-) mice. To investigate which origins of COMP contributed to atherosclerotic calcification, bone marrow transplantation was performed between ApoE-/and ApoE(-/-) COMP-/- mice. Enhanced calcification was observed in mice transplanted with ApoE(-/-) COMP-/- bone marrow compared with mice transplanted with ApoE(-/-) bone marrow, indicating that bone marrow-derived COMP may play a critical role in atherosclerotic calcification. Furthermore, microarray profiling of wild-type and COMP-/- macrophages revealed that COMP-deficient macrophages exerted atherogenic and osteogenic characters. Integrin beta 3 protein was attenuated in COMP-/- macrophages, and overexpression of integrin beta 3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, adeno-associated virus 2-integrin beta 3 infection attenuated atherosclerotic calcification in ApoE(-/-)COMP(-/-) mice. Mechanistically, COMP bound directly to beta-tail domain of integrin beta 3 via its C-terminus, and blocking of the COMP-integrin beta 3 association by beta-tail domain mimicked the COMP deficiency-induced shift in macrophage phenotypes. Similar to COMP deficiency in mice, transduction of adeno-associated virus 2-beta-tail domain enhanced atherosclerotic calcification in ApoE(-/-) mice. Conclusions: These results reveal that COMP deficiency acted via integrin beta 3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification.