Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation
Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation
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DOI：
10.1073/pnas.1019443108
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发表时间：
2011-02-01
影响因子：
11.1
通讯作者：
Mani, Arya
中科院分区：
文献类型：
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作者：
Keramati, Ali R.;Singh, Rajvir;Mani, Arya
血管平滑肌细胞（VSMC）增殖是动脉粥样硬化和其他血管病的重要事件。 PDGF信号传导是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) LRP6(R611C) 的突变，该突变会导致早期动脉粥样硬化。对人动脉粥样硬化冠状动脉的检查显示，LRP6 的表达显着增加，并且与 PDGF 受体 β (PDGFR-β) 共定位。进一步研究表明，野生型LRP6抑制PDGF反应，但LRP6(R611C)促进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，而LRP6(R611C)的功能严重受损。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是平滑肌中PDGF依赖性细胞周期调节的关键调节剂，并表明这种功能的丧失会导致人类早期动脉粥样硬化的发展。
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 beta (PDGFR-beta). 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-beta 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.