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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

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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References

  1. Multiple Risk Factor Intervention Trial Research Group. Relationship between baseline risk factors and coronary heart disease and total mortality in the Multiple Risk Factor Intervention Trial. Prev. Med. 15, 254–273 (1986).

    Article  Google Scholar 

  2. Borhani, N.O. in Atherosclerosis Beyond Cholesterol 3–16 (Audio Visual Medical Marketing, New York, 1992).

    Google Scholar 

  3. Chobanian, A.V. & Alexander, R.W. Exacerbation of atherosclerosis by hypertension: potential mechanisms and clinical implications. Arch. Int. Med. 156, 1952–1956 (1996).

    Article  CAS  Google Scholar 

  4. Chobanian, A.V. 1989 Corcoran Lecture: adaptive and maladaptive responses of the arterial wall to hypertension. Hypertension 15, 666–674 (1990).

    Article  CAS  Google Scholar 

  5. Chobanian, A.V. et al. Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit. Hypertension 14, 203–209 (1989).

    Article  CAS  Google Scholar 

  6. Brasen, J.H., Harsch, M. & Niendorf, A. Survival and cardiovascular pathology of heterozygous Watanabe heritable hyperlipidemic rabbits treated with pravastatin and probucol on a low-cholesterol (0.03%)-enriched diet. Virchows Arch. 432, 557–562 (1998).

    Article  CAS  Google Scholar 

  7. Shiomi, M., Ito, T., Shiraishi, M. & Watanabe, Y. Inheritability of atherosclerosis and the role of lipoproteins as risk factors in the development of atherosclerosis in WHHL rabbits: risk factors related to coronary atherosclerosis are different from those related to aortic atherosclerosis. Atherosclerosis 96, 43–52 (1992).

    Article  CAS  Google Scholar 

  8. Guyard-Dangeremont, V., Desrumaux, C., Gambert, P., Lallemant, C. & Lagrost, L. Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 120, 517–525 (1998).

    Article  Google Scholar 

  9. Moulin, P. Cholesteryl ester transfer protein: an enigmatic protein. Horm. Res. 45, 238–244 (1996).

    Article  CAS  Google Scholar 

  10. Inazu, A. et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N. Engl. J. Med. 323, 1234–1238 (1990).

    Article  CAS  Google Scholar 

  11. Yamashita, S. et al. Characterization of plasma lipoproteins in patients heterozygous for human plasma cholesteryl ester transfer protein (CETP) deficiency: plasma CETP regulates high-density lipoprotein concentrations and composition. Metabolism 40, 756–763 (1991).

    Article  CAS  Google Scholar 

  12. Zhong, S.B. et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J. Clin. Invest. 97, 2917–2923 (1996).

    Article  CAS  Google Scholar 

  13. Marotti, K.R. et al. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 364, 73–75 (1993).

    Article  CAS  Google Scholar 

  14. Plump, A.S. et al. Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler. Thromb. Vasc. Biol. 19,1105–110 (1999).

    Article  CAS  Google Scholar 

  15. Hayek, T. et al. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J. Clin. Invest. 96, 2071–2074 (1995).

    Article  CAS  Google Scholar 

  16. Lee, R.T. & Libby, P. The unstable atheroma. Arterios. Throm. Vasc. Biol. 17, 1859–1867 (1997).

    Article  CAS  Google Scholar 

  17. Herrera, V.L.M., Xie, H.X., Lopez, L.V., Schork, N.J. & Ruiz-Opazo, N. The α1 Na,K- ATPase gene is a susceptibility hypertension gene in the Dahl salt-sensitive rat. J. Clin. Invest. 102, 1102–1111 (1998).

    Article  CAS  Google Scholar 

  18. Lefer, D.J. & Granger, D.N. Monocyte rolling in early atherogenesis: vital role in lesion development. Circ. Res. 11, 1353–1355 (1999).

    Article  Google Scholar 

  19. Nakashima, Y., Raines, E.W., Plump, A.S., Breslow, J.L. & Ross, R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler. Thromb. Vasc. Biol. 18, 842–851 (1998).

    Article  CAS  Google Scholar 

  20. Nelken, N., Couglin, S., Gordon, D. & Wilcox J. Monocyte chemoattractant protein-1 in human atheromatous plaques. J. Clin. Invest. 88, 1121–1127 (1991).

    Article  CAS  Google Scholar 

  21. Shih, D.M., Welch, C. & Lusis, A.J. New insights into atherosclerosis from studies with mouse models. Mol. Med. Today (Elsevier Science Ltd.) 1, 364–372 (1995).

    Article  CAS  Google Scholar 

  22. Jiang, X.C. et al. Down-regulation of messenger RNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein. Mechanism to explain accumulation of lipoprotein B particles. J. Biol. Chem. 268, 27406–27412 (1993).

    CAS  Google Scholar 

  23. Grass, D.S. et al. Transgenic mice expressing both human apolipoprotein B and human CETP have a lipoprotein cholesterol distribution similar to that of normolipidemic humans. J. Lipid. Res. 36, 1082–1091 (1995).

    CAS  Google Scholar 

  24. Hayek, T. et al. An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-I genes in transgenic mice results in a profound CETP-mediated depression of high density cholesterol levels. J. Clin. Invest. 90, 505–510 (1992).

    Article  CAS  Google Scholar 

  25. Foger, B., Ritsch, A., Doblinger, A., Wessels, H. & Patsch, J.R. Relationship of plasma cholesteryl ester transfer protein to HDL cholesterol: studies in normotriglyceridemia and moderate hypertriglyceridemia. Arterioscler. Thromb. Vasc. Biol. 16, 1430–1436 (1996).

    Article  CAS  Google Scholar 

  26. Sechi, L.A. et al. Glucose metabolism and insulin receptor binding and mRNA levels in tissues of Dahl hypertensive rats. Am. J. Hypertens. 10, 1223–1230 (1997).

    Article  CAS  Google Scholar 

  27. Kitagawa, S., Yamaguchi, Y., Shinozuka, K, Kwon, Y.M. & Kunitomo, M. Dietary cholesterol enhances impaired endothelium-dependent relaxations in aortas of salt-induced hypertensive Dahl rats. Eur. J. Pharmacol. 297, 71–76 (1995).

    Article  Google Scholar 

  28. Reddick, R.L., Zhang, S.H. & Maeda, N. Atherosclerosis in mice lacking apoE. Evaluation of lesional development and progression. Arterioscler. Thromb. 14, 141–147 (1994).

    Article  CAS  Google Scholar 

  29. Nakashima, Y., Plump, A.S., Raines, E.W., Breslow, J.L. & Ross, R. ApoE-deficient mice develop lesions of all phases of atherosclerosis through the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994).

    Article  CAS  Google Scholar 

  30. Ebara, T, Ramakrishnan, R, Steiner, G & Shacter, NS . Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. J. Clin. Invest. 99, 2672–2681 (1997).

    Article  CAS  Google Scholar 

  31. Paigen, B., Morrow, A., Brandon, C., Mitchell, D. & Holmes, P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57, 65–73 (1985).

    Article  CAS  Google Scholar 

  32. Ong, G.L. & Mattes, M.J. Mouse strains with typical mammalian levels of complement activity. J. Immunol. Meth. 125, 147–158 (1991).

    Article  Google Scholar 

  33. Torzewski, K., Bowyer, D.E., Waltenberger, J. & Fizsimmons, C. Processes in atherogenesis: complement activation. Atherosclerosis 132, 131–138. (1997).

    Article  CAS  Google Scholar 

  34. Krauss, R.M. Triglycerides and atherogenic lipoproteins: Rational for lipid management. Am. J. Med. 105, 58S–62S (1998).

    Article  CAS  Google Scholar 

  35. Tropea, B.I. et al. Hypertension-enhanced monocyte adhesion in experimental atherosclerosis. J. Vasc. Surg. 23, 596–605 (1996).

    Article  CAS  Google Scholar 

  36. Capers, Q. et al. Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats. Hypertension 30, 1397–1402 (1997).

    Article  CAS  Google Scholar 

  37. Shioi, T. et al. Increased expression of interleukin-1 beta and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the hypertrophied and failing heart with pressure overload. Circ. Res. 81, 664–671 (1997).

    Article  CAS  Google Scholar 

  38. O'Brien, K.D. et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques: implications for the mode of progression of advanced coronary atherosclerosis. J. Clin. Invest. 92, 945–951 (1993).

    Article  CAS  Google Scholar 

  39. Schecter, A.D. et al. Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells. J. Biol. Chem. 272, 28568–28573 (1997).

    Article  CAS  Google Scholar 

  40. Buja, L.M. & Willerson, J.T. Role of inflammation in coronary plaque disruption. Circulation 89, 503–505 (1994).

    Article  CAS  Google Scholar 

  41. Boyle, J.J. Association of coronary plaque rupture and atherosclerotic inflammation. J. Pathol. 181, 93–99 (1997).

    Article  CAS  Google Scholar 

  42. Davies, H. & al-Tikriti, S. Coronary arterial pathology in the transplanted heart. Int. J. Cardiol. 25, 99–117 (1989).

    Article  CAS  Google Scholar 

  43. Russell, P.S., Chase, C.M., Winn, H.J. & Colvin, R.B. Coronary atherosclerosis in transplanted mouse hearts. I. Time course and immunogenetic and immunopathological considerations. Am. J. Pathol. 144, 260–274 (1994).

    CAS  Google Scholar 

  44. Atkinson, J.B. Accelerated arteriosclerosis after transplantation: the possible role of calcium channel blockers. Int. J. Cardiol. 62, S125–134 (1997).

    Article  Google Scholar 

  45. Drayna, D. et al. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature 327, 632–634 (1987).

    Article  CAS  Google Scholar 

  46. Zannis, V.I., Cole, S.F., Jackson, C., Kurnit, D.M. & Karathanasis, S.K. Distribution of apoA-I, apoC-II, apoC-III and apoE mRNA in human tissues. Time dependent induction of apoE mRNA by cultures of human monocyte-macrophages. Biochemistry 24, 4450–4455 (1985).

    Article  CAS  Google Scholar 

  47. Adari, H., Xiang, X.H., Ruiz-Opazo, N., Herrera, V.L.M. & Makrides, S.C. in Vascular Endothelium: Pharmacologic and Genetic Manipulations (eds. Catravas, J.D., Callow, A.D. & Ryan, U.S.) 235–236 (NATO ASI Series, Plenum, New York, 1998).

    Book  Google Scholar 

  48. Krauss, R.M., Grunfeld, C., Doerrler, W.T. & Feingold, K.R. Tumor necrosis factor acutely increases plasma levels of very low density lipoproteins of normal size and composition. Endocrinology 127, 1016–1021 (1990).

    Article  CAS  Google Scholar 

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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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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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