| First Author | Fu Y | Year | 2016 |
| Journal | Circ Res | Volume | 119 |
| Issue | 2 | Pages | 261-76 |
| PubMed ID | 27151399 | Mgi Jnum | J:250705 |
| Mgi Id | MGI:6100855 | Doi | 10.1161/CIRCRESAHA.115.308021 |
| Citation | Fu Y, et al. (2016) Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification. Circ Res 119(2):261-76 |
| abstractText | 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 beta3 protein was attenuated in COMP(-/-) macrophages, and overexpression of integrin beta3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, adeno-associated virus 2-integrin beta3 infection attenuated atherosclerotic calcification in ApoE(-/-)COMP(-/-) mice. Mechanistically, COMP bound directly to beta-tail domain of integrin beta3 via its C-terminus, and blocking of the COMP-integrin beta3 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 beta3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification. |
