Abstract 19002: LRP6 Mutation (LRP6R611C) Leads to PDGF Dependent Vascular Smooth Muscle Cell Hyperproliferation and Atherosclerosis
A loss of function mutation in the Wnt co-receptor Low Density Lipoprotein Receptor Related Protein 6, (LRP6R611C) causes early atherosclerosis and metabolic syndrome in humans. We have generated LRP6R611C mice with homologous recombination. LRP6R611C mice demonstrate enhanced vascular smooth muscle cell (VSMC) proliferation, and exaggerated neointima formation upon carotid injury mice and on LDLR knockout background develop accelerated atherosclerosis compared to their respective controls. The aorta of LRP6R611C mice exhibits a highly proliferative media marked by an increases in PDGFRβ and ELK1 expression along with decreased myocardin expression. These findings correlate with reduced α-SMA and increased vimentin in the aortic media, indicating proliferative phenotype of VSMCs. Furthermore, in LRP6R611C mice the aortic adventitia is loaded with PDGFRβ positive cells along with abundance of Sca1 positive progenitor cells in the aortic intimal and adventitial layers. Ex vivo, cultured LRP6R611C VSMCs exhibit increased expression of PDGF-BB and its transcriptional regulator SP1. These findings suggest that LRP6R611C promotes maintenance of progenitor cellin the aorta and enhances VSMC proliferation through activated PDGF signaling. Interestingly, the levels of PDGF-BB were also significantly increased in the macrophages as well as plasma of the LRP6R611C mice. LRP6R611C macrophages exhibited increased uptake of ox-LDL and augmented expression of vimentin, a regulator of intracellular LDL transport. Thus,LRP6R611C mutation indicatesa single gene defect in Wnt pathway leading to a major aberration in PDGF dependent signaling thereby predisposing to atherosclerosis.
- © 2012 by American Heart Association, Inc.