Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation.

Abstract

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.

• Authors: Ali R Keramati, Rajvir Singh, Aiping Lin, Saeed Faramarzi, Zhi-jia Ye, Shrikant Mane, George Tellides, Richard P Lifton, Arya Mani
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 5 Pg. 1914-8 (Feb 01 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21245321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• LDL-Receptor Related Proteins
• LRP6 protein, human
• Low Density Lipoprotein Receptor-Related Protein-6
• Platelet-Derived Growth Factor
• RNA, Messenger
• Cyclin D1
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Atherosclerosis (pathology, physiopathology)
• Cell Proliferation
• Cyclin D1 (metabolism)
• Humans
• Immunohistochemistry
• LDL-Receptor Related Proteins (physiology)
• Low Density Lipoprotein Receptor-Related Protein-6
• Muscle, Smooth, Vascular (cytology)
• Platelet-Derived Growth Factor (physiology)
• RNA, Messenger (genetics)
• Receptor, Platelet-Derived Growth Factor beta (genetics)
• Signal Transduction