Abstract 5811: Dual Function of Bone Morphogenetic Protein-2 in the Progression of Atherosclerotic Lesion and Atherosclerotic Intimal Calcification in vivo
Vascular calcification is one of the most important risk factor for the cardiovascular diseases as well as a predictor of all-cause death. Recent findings suggest that bone calcification regulatory factors, locally expressed in blood vessels, play unique roles in the formation of vascular calcification. However, detailed molecular mechanisms, that regulate the intimal calcification associated with atherosclerosis, remain unclear. We first investigated the potential role of de-differentiated VSMCs in the formation of atherosclerotic intimal calcification. In vitro studies revealed that bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblastic differentiation was markedly up-regulated in the de-differentiated VSMCs comparing to the differentiated VSMCs. We therefore generated the BMP-2 transgenic mice in which BMP-2 expression was driven by αSMA-promoter, and mated them with ApoE-knockout mice to obtained BMP-2-Tg/ApoE-KO mice. After 8 weeks of high fat diet, atherosclerotic intimal calcification was not detectable even in BMP-2-Tg/ApoE-KO mice. Somewhat unexpectedly, atherosclerosis was significantly attenuated in BMP-2-Tg/ApoE-KO mice as compared to ApoE-KO mice. The number of αSMA-positive VSMCs and macrophages in the atherosclerotic intima was significantly reduced in BMP-2-Tg/ApoE-KO. Also, we found that BMP-2 inhibits the uptake of acetylated LDL in macrophage, and protects endothelial cells from apoptosis in vitro. Of note, when fed with high fat diet for 30 weeks, atherosclerotic intimal calcification was greater in BMP-2-Tg/ApoE-KO than in ApoE-KO mice, whereas the size of atherosclerotic lesion was not different between them. In conclusion, we revealed the dual function of BMP-2 in the atherosclerosis
anti-atherogenic function in the early atherosclerotic lesion, presumably through
reducing the proliferation of VSMCs
inhibiting the lipid-uptake in macrophage
protecting endothelial cells from apoptosis, and
pro-calcification function in the advanced atherosclerotic intima.