Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):1914-8. doi: 10.1073/pnas.1019443108. Epub 2011 Jan 18.
Vascular smooth muscle cell (VSMC) proliferation is an important event in atherosclerosis and other vasculopathies. PDGF signaling is a key mediator of SMC proliferation, but the mechanisms that control its activity remain unclear. We previously identified a mutation in LDL receptor-related protein 6 (LRP6), LRP6(R611C), that causes early atherosclerosis. Examination of human atherosclerotic coronary arteries showed markedly increased expression of LRP6 and colocalization with PDGF receptor β (PDGFR-β). Further investigation showed that wild-type LRP6 inhibits but LRP6(R611C) promotes VSMC proliferation in response to PDGF. We found that wild-type LRP6 forms a complex with PDGFR-β and enhances its lysosomal degradation, functions that are severely impaired in LRP6(R611C). Further, we observed that wild-type and mutant LRP6 regulate cell-cycle activity by triggering differential effects on PDGF-dependent pathways. These findings implicate LRP6 as a critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and indicate that loss of this function contributes to development of early atherosclerosis in humans.
血管平滑肌细胞（VSMC）增殖是动脉粥样硬化和其他血管病变的一个重要事件。血小板衍生生长因子（PDGF）信号是 SMC 增殖的关键介质，但控制其活性的机制仍不清楚。我们之前发现了 LDL 受体相关蛋白 6（LRP6）的一个突变，LRP6（R611C），它导致早期动脉粥样硬化。对人类动脉粥样硬化性冠状动脉的检查显示，LRP6 的表达明显增加，并与 PDGF 受体β（PDGFR-β）共定位。进一步的研究表明，野生型 LRP6 抑制，但 LRP6（R611C）促进对 PDGF 的 VSMC 增殖。我们发现野生型 LRP6 与 PDGFR-β 形成复合物，并增强其溶酶体降解，LRP6（R611C）严重损害了这些功能。此外，我们观察到野生型和突变型 LRP6 通过触发对 PDGF 依赖性途径的不同影响来调节细胞周期活性。这些发现表明 LRP6 是 PDGF 依赖性调节平滑肌细胞周期的关键调节剂，并表明该功能的丧失导致人类早期动脉粥样硬化的发展。
