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 (BM) transplantation was performed between ApoE−/− and ApoE−/−COMP−/− mice. Enhanced calcification was observed in mice transplanted with ApoE−/−COMP−/− BM compared to mice transplanted with ApoE−/− BM, indicating that BM-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 β3 protein was attenuated in COMP−/− macrophages, and overexpression of integrin β3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, AAV2-integrin β3 infection attenuated atherosclerotic calcification in ApoE−/−COMP−/− mice. Mechanistically, COMP bound directly to β-tail domain of integrin β3 via its C-terminus, and blocking of the COMP-integrin β3 association by β-tail domain mimicked the COMP deficiency-induced shift in macrophage phenotypes. Similar as COMP deficiency in mice, transduction of AAV2-β-tail domain enhanced atherosclerotic calcification in ApoE−/− mice.
Conclusions: These results reveal that COMP deficiency acted via integrin β3 to drive macrophages towards the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification.
- Received November 14, 2015.
- Revision received May 3, 2016.
- Accepted May 5, 2016.