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Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein

Nature Medicine volume 5, pages 1383–1389 (1999)Cite this article

Abstract

The acceleration of atherosclerosis by polygenic (essential) hypertension is well-characterized in humans; however, the lack of an animal model that simulates human disease hinders the elucidation of pathogenic mechanisms. We report here a transgenic atherosclerosis–polygenic hypertension model in Dahl salt-sensitive hypertensive rats that overexpress the human cholesteryl ester transfer protein (Tg[hCETP]DS). Male Tg[hCETP]DS rats fed regular rat chow showed age-dependent severe combined hyperlipidemia, atherosclerotic lesions, myocardial infarctions and decreased survival. These findings differ from various mouse atherosclerosis models, demonstrating the necessity of complex disease modeling in different species. The data demonstrate that cholesteryl ester transfer protein can be proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in the pathogenesis of atherosclerosis in Tg[hCETP]DS rats substantiates epidemiological observations in humans.

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Figure 1: Four transgenic Dahl S rat founder lines with the hCETP transgene.
Figure 2: Comparative densitometric scans.
Figure 3: Atherosclerotic lesions in aorta and coronary and intramyocardial arteries of transgenic Tg53 Dahl S rats and non-transgenic Dahl S rats 6 months old, fed regular rat chow.
Figure 4: High-power magnification showing the histopathologic characteristics of coronary heart disease in Tg53 rat hearts.
Figure 5: Immunohistochemical analysis of serial sections of a representative coronary artery occlusive fibroatheromatous lesion.

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Acknowledgements

We thank A.V. Chobanian, J. Loscalzo, C. Rittershaus, L. Thomas and A. Callow for many discussions; and C.M. Reardon and A. Tsikoudakis for technical assistance. This work was supported by the National Institutes of Health and Evans Research Development Fund.

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Authors and Affiliations

  1. Whitaker Cardiovascular Institute, 700 Albany Street, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Victoria L. M. Herrera, Savvas C. Makrides, Hou Xiang Xie, Una S. Ryan & Nelson Ruiz-Opazo

  2. Avant Immunotherapeutics, 119 4th Street, Needham, 02494, Massachusetts, USA

    Savvas C. Makrides, Hedy Adari & Una S. Ryan

  3. Department of Molecular Medicine, Lawrence Berkeley National Laboratory, University of California, Berkeley, 94720, California, USA

    Ronald M. Krauss

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Correspondence to Victoria L. M. Herrera.

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Herrera, V., Makrides, S., Xie, H. et al. Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat Med 5, 1383–1389 (1999). https://doi.org/10.1038/70956

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