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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, OBJECTIVE, RESULTS. Meshes: Animals, Atherosclerosis, Cartilage Oligomeric Matrix Protein, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Vascular Calcification.
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Does shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency drive Atherosclerotic Calcification? Context: 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. To investigate whether COMP affects atherosclerotic calcification. 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 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 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 to COMP deficiency in mice, transduction of adeno-associated virus 2-β-tail domain enhanced atherosclerotic calcification in ApoE(-/-) mice.
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These results reveal that COMP deficiency acted via integrin β3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification. Final Decision: yes