Reduced calcification and osteogenic features in advanced atherosclerotic plaques of mice with macrophage-specific loss of TRPC3.

BACKGROUND AND AIMS

Recent in vitro studies have showed that in macrophages, deletion of the non-selective Ca-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.