The multifaceted role of macrophages in cardiovascular calcification

BACKGROUND AND AIMS: Recent in vitro studies have showed that in macrophages deletion of the non-selective Ca(2+)-permeable channel TRPC3 impairs expression of the osteogenic protein BMP-2. The pathophysiological relevance of this effect in atherosclerotic plaque calcification remains to be determined. METHODS: We used Ldlr(−/−) mice with macrophage-specific loss of TRPC3 (MacTrpc3(−/−)/Ldlr(−/−)) to examine the effect of macrophage Trpc3 on plaque calcification and osteogenic features in advanced atherosclerosis. RESULTS: After 25 weeks on high fat diet, aortic root plaques in MacTrpc3(−/−)/Ldlr(−/−) mice showed reduced size, lipid and macrophage content compared to controls. Plaque calcification was decreased in MacTrpc3(−/−)/Ldlr(−/−) mice, and this was accompanied by marked reduction in BMP-2, Runx-2 and phospho-SMAD1/5 contents within macrophage-rich areas. Expression of Bmp-2 and Runx-2 was also reduced in bone marrow-derived macrophages from MacTrpc3(−/−)/Ldlr(−/−) mice. CONCLUSIONS: These findings show that, in advanced atherosclerosis, selective deletion of TRPC3 in macrophages favors plaque regression and impairs the activity of a novel macrophage-associated, BMP-2-dependent mechanism of calcification.