on September 2, 2003
Published online before print September 2, 2003, doi: 10.1161/01.CIR.0000089085.76320.4E
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Submitted on September 9, 2002
From the Department of Molecular Cardiology (O.I.S., I.K., E.J.T., E.F.P.), the Cerebrovascular Center (S.Y.D., K.K., D.J.), the Department of Cardiovascular Medicine (E.J.T.), and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology (O.I.S., I.K., E.J.T., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio. * To whom correspondence should be addressed. E-mail: plowe{at}ccf.org.
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.
Revised on May 8, 2003
Accepted on May 16, 2003
Thrombospondin-4 and Its Variants. Expression and Differential Effects on Endothelial Cells
Olga I. Stenina PhD,
Key words: cells, adhesion • cells, proliferation • atherosclerosis • extracellular matrix • endothelium
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