期刊
CIRCULATION
卷 108, 期 12, 页码 1514-1519出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000089085.76320.4E
关键词
cells, adhesion; cells, proliferation; atherosclerosis; extracellular matrix; endothelium
资金
- NHLBI NIH HHS [R01-HL-51614] Funding Source: Medline
- NIDDK NIH HHS [K01-DK-62128] Funding Source: Medline
- NINDS NIH HHS [R01-NS-38195] Funding Source: Medline
- DS NIH HHS [R01-NINDS-43284] Funding Source: Medline
Background-In a recent large-scale genetic association study, a single nucleotide polymorphism in the thrombospondin-4 (TSP-4) gene, resulting in a proline-for-alanine substitution at position 387, was associated with a significantly increased risk for premature atherosclerosis. TSP-4 had not previously been implicated in vascular pathology, and very little information is available on its expression and functions. Methods and Results-The goal of this study was to assess TSP-4 expression in vessel wall and to identify differences in functions of TSP-4 variants that could account for the proatherogenic effects of the (P387) TSP-4 variant. TSP-4 expression was demonstrated in human endothelial cells (ECs) and vascular smooth muscle cells from brain blood vessels and coronary arteries. (P387) TSP-4 and its fragment (residues 326 to 722), but not the A(387) forms, suppressed EC adhesion and proliferation. The (P387) TSP-4 was more active in inducing the phosphorylation of focal adhesion kinase, consistent with inhibition of proliferation. Both variant fragments increased the proliferation of human aortic smooth muscle cells. Conclusions-TSP-4 is expressed by vascular cells and influences the vessel wall by modulating the proliferation of ECs and smooth muscle cells. The A387P substitution is a gain-of-function mutation, favoring a form of TSP-4 that interferes with EC adhesion and proliferation and may thereby be proatherogenic.
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