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Volume 271, Number 49, Issue of December 6, 1996 pp. 31367-31371
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Feedback Mechanism of Focal Vascular Lesion Formation in Transgenic Apolipoprotein(a) Mice

(Received for publication, August 2, 1996, and in revised form, September 24, 1996)

Richard M. Lawn , Andrew D. Pearle , Lawrence L. Kunz ^¶ , Edward M. Rubin , Jill Reckless ^** , James C. Metcalfe ^** and David J. Grainger ^**

From the  Falk Cardiovascular Research Center, Stanford University, Stanford, California 94305-5246, ^¶ NeoRx Corporation, Seattle, Washington 98119, the  Lawrence Berkeley Laboratory, Berkeley, California 94720, and the ^** Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom

Apolipoprotein(a) (apo(a)), the distinguishing protein of atherogenic lipoprotein(a), directs accumulation of the lipoprotein(a) particle to sites in the arterial wall where atherosclerotic lipid lesions develop in man and in transgenic mice expressing human apo(a). It has been proposed that focal apo(a) accumulation in the transgenic mouse vessel wall causes the observed severe local inhibition of transforming growth factor- (TGF-) activity and the consequent activation of the smooth muscle cells, which subsequently accumulate lipid to form lesions if the mice are fed a high fat diet. We show that blocking formation of these vascular lesions by two independent mechanisms, tamoxifen treatment and increasing high density lipoprotein, also abolishes apo(a) accumulation, inhibition of TGF- activity, and activation of smooth muscle cells. The data are consistent with a feedback mechanism in which an initial accumulation of apo(a) inhibits local TGF- activity, leading to further accumulation of apo(a). Breaking the feedback loop prevents smooth muscle cell activation and therefore lipid lesion development.

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