Feedback Mechanism of Focal Vascular Lesion Formation in Transgenic Apolipoprotein(a) Mice*
- 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
- § To whom correspondence should be addressed: Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305-5246. Tel.: 415-725-4494; Fax: 415-725-1599; E-mail: richard.lawn{at}forsythe.stanford.edu.
Abstract
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-β (TGF-β) 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-β 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-β activity, leading to further accumulation of apo(a). Breaking the feedback loop prevents smooth muscle cell activation and therefore lipid lesion development.
Footnotes
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↵* This work was supported by National Institutes of Health grants (to R. M. L. and E. M. R.) and Wellcome Trust and British Heart Foundation grants (to J. C. M. and D. J. G.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- Lp(a)
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lipoprotein(a)
- apo
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apolipoprotein
- TGF-β
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transforming growth factor-β
- HDL
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high density lipoprotein.
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↵2 D. J. Grainger, R. M. Lawn, and L. McEvoy, unpublished data.
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↵3 It should be noted that in this model, tamoxifen does not alter the circulating levels of apo(a), since this derives from transgenic expression of apo(a) cDNA driven by the transferrin promoter. However, tamoxifen has recently been shown to lower the concentration of circulating Lp(a) in humans (46) by inhibiting transcription of the apo(a) gene (47). Hence, tamoxifen and its analogs may exert a doubly protective effect against the cardiovascular risk of elevated Lp(a).
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- Received August 2, 1996.
- Revision received September 24, 1996.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
