Description: 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 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. 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.

Description: Objective— Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. Approach and Results— We observed that the nicotinic acid–induced increase in blood flow was substantially reduced in Trpv1 –/– knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions— Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.