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J. Biol. Chem., Vol. 279, Issue 20, 21651-21657, May 14, 2004

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Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction^*

Natalya V. Narizhneva||, Vicky J. Byers-Ward, Martin J. Quinn, Frank J. Zidar, Edward F. Plow, Eric J. Topol¶, and Tatiana V. Byzova**

From the Departments of Molecular Cardiology and Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195

A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated with early onset myocardial infarction.

Received for publication, October 8, 2003 , and in revised form, March 5, 2004.

^* This work was supported in part by National Institutes of Health Grant HL071625 (to T. V. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Recipient of an American Heart Association Fellowship (0325229B).

^¶ To whom correspondence may be addressed: Dept. of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-9490; Fax: 216-445-9595; E-mail: topole{at}ccf.org.

^** To whom correspondence may be addressed: Joseph J. Jacobs Ctr. for Thrombosis and Vascular Biology, Dept. of Molecular Cardiology, Cardiology and Taussig Cancer Ctr., Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-9490; Fax: 216-445-9595.

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