Details

Autor(en) / Beteiligte

• Fu, Yi
• Gao, Cheng
• Liang, Ying
• Wang, Meili
• Huang, Yaqian
• Ma, Wei
• Li, Tuoyi
• Jia, Yiting
• Yu, Fang
• Zhu, Wanlin
• Cui, Qinghua
• Li, Yanhui
• Xu, Qingbo
• Wang, Xian
• Kong, Wei

Titel

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

Ist Teil von

• Circulation research, 2016-07, Vol.119 (2), p.261-276

Ort / Verlag

United States: American Heart Association, Inc

Erscheinungsjahr

2016

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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:ApoECOMP 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 ApoECOMP mice. Enhanced calcification was observed in mice transplanted with ApoECOMP 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 β3 protein was attenuated in COMP macrophages, and overexpression of integrin β3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, adeno-associated virus 2–integrin β3 infection attenuated atherosclerotic calcification in ApoECOMP 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 to COMP deficiency in mice, transduction of adeno-associated virus 2–β-tail domain enhanced atherosclerotic calcification in ApoE mice. CONCLUSIONS:These results reveal that COMP deficiency acted via integrin β3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification.