Skip to main content
SpringerLink
Log in

Cardiovascular disease in the JCR:LA-cp rat

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+)are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of a-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Reaven GM, Chen Y-DI: Insulin resistance, its consequences, and coronary heart disease. Circulation 93: 1780–1783, 1996

    PubMed  Google Scholar 

  2. Steiner G: Hyperinsulinernia and hypertriglyceridemia. J Int Med 736(Suppl): 23–26, 1994

    Google Scholar 

  3. Taegtmeyer H: Insulin resistance and atherosclerosis. Common roots for two common diseases. Science 93: 17771–11779, 1996

    Google Scholar 

  4. Stern MP: Diabetes and cardiovascular disease: The 'common soil' hypothesis. Diabetes 44: 369–374, 1995

    PubMed  Google Scholar 

  5. Russell JC, Ahuja SK, Manickavel V, Rajotte RV, Amy RM: Insulin resistance and impaired glucose tolerance in the atherosclerosis prone LA/N-corpulent rat. Arteriosclerosis 7: 620–626, 1987

    PubMed  Google Scholar 

  6. Russell JC, Graham S, Hameed M: Abnormal insulin and glucose metabolism in the JCR:LA-corpulent rat. Metabolism 43: 538–543, 1994

    PubMed  Google Scholar 

  7. Russell JC, Manickavel V, Koeslag DG, Amy RM: Effects of advancing age and severe food restriction on pathological processes in the insulin resistant JCR:LA-corpulent rat. Diabetes Res 15: 53–62, 1990

    PubMed  Google Scholar 

  8. McNamee CJ, Kappagoda CT, Kunjara R, Russell JC: Defective endothelium-dependent relaxation in the JCR:LA-corpulent rat. Circ Res 74: 1126–1132, 1994

    PubMed  Google Scholar 

  9. Russell JC, Amy RM: Early atherosclerotic lesions in a susceptible rat model: The LA/N-corpulent rat. Atherosclerosis 60: 119–129, 1986

    PubMed  Google Scholar 

  10. Russell JC, Amy RM: Myocardial and vascular lesions in the LA/N-corpulent rat. Can J Physiol Pharmacol 64: 1272–1280, 1986

    PubMed  Google Scholar 

  11. Pederson RA, Campos RV, Buchan AMJ, Chisholm CB, Russell JC, Brown JC: Comparison of the enteroinsular axis in two strains of obese rats: The fatty Zucker and JCR:LA-corpulent. Int J Obes 15: 461–470, 1991

    PubMed  Google Scholar 

  12. Russell JC, Amy RM, Michaelis OE, McCune SM, Abraham AA: Myocardial disease in the corpulent strains of rats. In: E Shafrir (ed). Frontiers in Diabetes Research: Lessons from Animal Diabetes III. Smith-Gordon, London, 1990, pp 402–407

    Google Scholar 

  13. Russell JC: The atherosclerosis-prone JCR:LA-corpulent rat. In: FP Woodford, J Davignon and A Sniderman (eds). Atherosclerosis X Proceedings-of the 10th International Symposium on Atherosclerosis. Elsevier Science, Amsterdam, 1995, pp 121–125

    Google Scholar 

  14. Amy RM, Dolphin PJ, Pederson RA, Russell JC: Atherogenesis in two strains of obese rats: The fatty Zucker and LA/N-corpulent. Atherosclerosis 69: 199–209, 1988

    PubMed  Google Scholar 

  15. Greenhouse DD, Michaelis OE, Peterson RG: The development of fatty and corpulent rat strains. In: CT Hansen and OE Michaelis (eds). New Models of Genetically Obese Rats for Studies in Diabetes, Heart Disease, and Complications of Obesity. National Institutes of Health, Bethesda, 1988, pp 3–6

    Google Scholar 

  16. Elwood KC, Michaelis OE, Emberland JJ, Bhathena SJ: Hormonal and lipogenic and gluconeogenic enzyme responses in LA/N-corpulent rats. Proc Soc Exp Biol Med 179: 163–167, 1985

    PubMed  Google Scholar 

  17. Michaelis OE, Elwood KC, Judge JM, Schoene NW, Hansen CT: Effect of dietary sucrose on the SHR/N-corpulent rat – A new model for insulin resistance. Amer J Clin Nutr 39: 612–618, 1983

    Google Scholar 

  18. Absher PM, Schneider DJ, Russell JC, Sobel BE: Increased proliferation of explanted vascular smooth muscle cells: A marker presaging atherogenesis. Atherosclerosis 131: 187–194, 1997

    PubMed  Google Scholar 

  19. Dolphin PJ, Amy RM, Russell JC: The effects of age and sex on the serum lipids and lipoproteins of the male and female JCR:LA-corpulent rat. Biochim Biophys Acta 1042: 99–106, 1990

    PubMed  Google Scholar 

  20. Russell JC, Koeslag DG, Amy RM, Dolphin PJ: Plasma lipid secretion and clearance in the hyperlipidemic JCR:LA-corpulent rat. Arteriosclerosis 9: 869–876, 1989

    PubMed  Google Scholar 

  21. Russell JC, Dolphin PJ, Hameed M, Stewart B, Koeslag DG, Rose-Kahn G, Bar-Tana J: The hypolipidemic effect of #x03B2;, #x03B2;´-tetramethyl hexadecanedioic acid (MEDICA 16) in hyperlipidemic JCR:LA-corpulent rats. Arteriosclerosis 11: 602–609, 1991

    Google Scholar 

  22. Russell JC, Amy RM, Graham SE, Dolphin PJ, Bar-Tana J: Inhibition of atherosclerosis and myocardial lesions in the JCR:LA-cp rat by #x03B2;, #x03B2;´-tetramethylhexadecanedioic acid (MEDICA 16). Arterioscler Thromb Vasc Biol 15: 918–923, 1995

    PubMed  Google Scholar 

  23. Iida M, Murakami T, Ishida K, Mizuno A, Kuwajima M, Shima K: Substitution at codon 260 (glutamine → proline) of the leptin receptor (OB-R) cDNA is the only mutation found in the Zucker fatty (fa/fa) rat. Biochem Biophys Res Comm 224: 597–604, 1996

    PubMed  Google Scholar 

  24. Wu-Peng, XS, Chua SC Jr, Okada N, Liu S-M, Nicolson M, Leibel RL: Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr). Diabetes 46: 513–518, 1997

    PubMed  Google Scholar 

  25. Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M: Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 46: 313–316, 1997

    PubMed  Google Scholar 

  26. Chan CB, MacPhail RM, Kibenge MT, Russell JC: Increased glucose phosphorylating activity correlates with insulin secreting capacity of male JCR:LA-corpulent rat islets. Can J Physiol Pharmacol 73: 501–508, 1995

    PubMed  Google Scholar 

  27. Ahuja S, Manickavel V, Amy RM, Russell JC: Age-related qualitative and quantitative changes in the endocrine pancreas of the LA/ N-corpulent rat. Diabetes Res 6: 137–144, 1987

    PubMed  Google Scholar 

  28. Vance JE, Russell JC: Hypersecretion of VLDL, but not HDL, by hepatocytes from the JCR:LA-corpulent rat. J Lipid Res 31: 1491–1501, 1990

    PubMed  Google Scholar 

  29. Russell JC, Graham SE, Dolphin PJ, Brindley DN: Effects of benfluorex on serum triacylglycerols and insulin sensitivity in the corpulent rat. Can J Physiol Pharmacol 74: 879–886, 1996

    PubMed  Google Scholar 

  30. Bougeois CS, Wiggins D, Hems R, Gibbons GR: VLDL output by hepatocytes from obese Zucker rats is resistant to the inhibitory effects of insulin. Am J Physiol 269: E208–E215, 1995

    PubMed  Google Scholar 

  31. Williams G, Shellard L, Lewis DA, McKibbin PE, McCarthy HD, Koeslag DG, Russell JC: Hypothalamic neuropeptide Y disturbances in the obese cp/cp JCR:LA-corpulent rat. Peptides 13: 537–540, 1992

    PubMed  Google Scholar 

  32. Williams G, Cardoso H, Domin J, Ghatei MA, Russell JC, Bloom SR: Disturbances of regulatory peptides in the hypothalamus of the JCR:LA-corpulent rat. Diabetes Res 15: 1–7, 1990

    PubMed  Google Scholar 

  33. Russell JC, Amy RM, Manickavel V, Dolphin PJ, Epling WF, Pierce D, Boer D: Prevention of myocardial disease in the JCR:LA-corpulent rat by running. J Appl Physiol 66: 1649, 1989

    PubMed  Google Scholar 

  34. Russell JC, Amy RM: Early atherosclerotic lesions in a susceptible rat model: The LA/N-corpulent rat. Atherosclerosis 60: 119–129, 1988

    Google Scholar 

  35. Russell JC, Amy RM, Dolphin PJ: Effect of n-3 fatty acids on atherosclerosis prone JCR:LA-corpulent rats. Exp Mol Pathol 55: 285–293, 1991

    PubMed  Google Scholar 

  36. Russell JC, Koeslag DG, Dolphin PJ, Amy RM: Beneficial effects of acarbose in the atherosclerosis prone JCR:LA-corpulent rat. Metabolism 43: 218–223, 1993

    Google Scholar 

  37. Russell JC, Amy RM, Manickavel V, Dolphin PJ: Effects of chronic ethanol consumption in atherosclerosis-prone JCR:LA-corpulent rat. Arteriosclerosis 9: 1221–1228, 1989

    Google Scholar 

  38. Brindley DN, Hales P, Al-Sieni AI, Russell JC: Sustained decreases in body weight and circulating insulin, glucose, triacylglycerol and cholesterol in JCR:LA-corpulent rats chronically treated with D-fenfluramine. Br J Pharmacol 105: 679–685, 1992

    PubMed  Google Scholar 

  39. Russell JC, Graham SE, Dolphin PJ, Amy RM, Wood GO, Brindley DN: Antiatherogenic effects of long-term benfluorex treatment in male insulin resistant JCR:LA-cp rats. Atherosclerosis 132: 187–197, 1997

    PubMed  Google Scholar 

  40. Sowers JR, Sowers PS, Peuler JD: Role of insulin resistance and hyperinsulinemia in development of hypertension and atherosclerosis. J Lab Clin Med 123: 647–652, 1994

    PubMed  Google Scholar 

  41. Russell JC, Graham S, Stewart B, Dolphin PJ: Sexual dimorphism in the metabolic response to the calcium channel antagonists, diltiazem and clentiazem, by hyperlipidemic JCR:LA-cp rats. Biochim Biophys Acta 1258: 199–205, 1995

    PubMed  Google Scholar 

  42. Russell JC, Koeslag DG, Dolphin PJ, Amy RM: Prevention of myocardial lesions in JCR:LA-corpulent rats by nifedipine. Arteriosclerosis 10: 658–664, 1990

    PubMed  Google Scholar 

  43. Russell JC, Dolphin PJ, Graham SE, Amy RM: Cardioprotective and hypolipidemic effects of nisoldipine in the JCR:LA-cp rat. J Cardiovasc Pharmacol 29: 586–592, 1997

    PubMed  Google Scholar 

  44. Linz W, Martorana PA, Schölkens BA. Local inhibition of bradykinin degradation in ischemic hearts. J Cardiovasc Pharmacol 15(6): S99–S109, 1990

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of Alberta, Edmonton, Alberta, USA

    James C. Russell & Sandra E. Graham

  2. Department of Pathology, McMaster University, Hamilton, Ontario, Canada

    Mary Richardson

Authors
  1. James C. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra E. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Russell, J.C., Graham, S.E. & Richardson, M. Cardiovascular disease in the JCR:LA-cp rat. Mol Cell Biochem 188, 113–126 (1998). https://doi.org/10.1023/A:1006828724405

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006828724405

Search

Navigation