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J. Biol. Chem., Vol. 279, Issue 53, 55187-55195, December 31, 2004

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Stimulation of Vascular Smooth Muscle Cell Proliferation and Migration by Apolipoprotein(a) Is Dependent on Inhibition of Transforming Growth Factor- Activation and on the Presence of Kringle IV Type 9^*

Caroline H. O'Neil, Michael B. Boffa, Mark A. Hancock, J. Geoffrey Pickering¶, and Marlys L. Koschinsky¶||

From the Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada and The Robarts Research Institute, London, Ontario N6A 5K8, Canada

Elevated plasma concentrations of lipoprotein(a) are a risk factor for the development of a variety of atherosclerotic disorders. Despite intensive study, the mechanisms by which lipoprotein(a) promotes these disorders remain to be unequivocally defined. It has been demonstrated that lipoprotein(a), through its unique constituent apolipoprotein(a) (apo(a)), stimulates vascular smooth muscle cell (SMC) migration and proliferation. These effects arise from the ability of apo(a) to inhibit the formation of active transforming growth factor (TGF-) from its latent precursor, which in turn is caused by the ability of apo(a) to decrease the formation of plasmin from its precursor plasminogen. We utilized a battery of recombinant apo(a) variants that represent systematic deletions of the various domains in the molecule to further probe the mechanism underlying the effect of apo(a) on SMC responses. All recombinant apo(a) variants that contained kringle IV type 9 were able to stimulate SMC proliferation and migration and to decrease the formation of active TGF-; conversely all recombinant apo(a) variants lacking kringle IV type 9 had no effect on these parameters. The kringle IV type 9-dependent effects of apo(a) on SMC proliferation required the presence of plasminogen, suggesting for the first time that this kringle mediates the ability of apo(a) to inhibit pericellular plasmin formation.

Received for publication, August 26, 2004 , and in revised form, October 20, 2004.

^* This work was supported by Heart and Stroke Foundation of Ontario Grants T-4408 (to M. L. K.) and T-4458 (to J. G. P.). 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.

^¶ Career Investigators of the Heart and Stroke Foundation of Ontario.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Rm. A208, Botterell Hall, Queen's University, Kingston, Ontario K7L 3N6 Canada. Tel.: 613-533-6586; Fax: 613-533-2987; E-mail: mk11{at}post.queensu.ca.

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