CARDIOVASCULAR-DISEASE IN THE JCR-LA-CP RAT

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 homozyg ous, for the gene (cp/cp) become obese, insulin resistant, and hypertr iglyceridemic. Heterozygotes or homozygous normal rats (+/+)are lean a nd metabolically normal. The JCR:LA-cp rat is unique in the developmen t of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly co rrelated with the hyperinsulinemia, which develops as the animals matu re from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the post prandial glucose and insulin responses through the use of(x-glucosidas e inhibitors. Any treatment that reduces plasma insulin levels is asso ciated with a reduction in cardiovascular disease. In contrast, a redu ction in plasma triglyceride concentrations, alone, has no effect on e nd-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, a re, however, sensitive to cholesterol in the diet, unlike other strain s that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperpl astic and activated and migrate into the intimal space. Our findings s uggest that susceptibility to cardiovascular disease requires hypermsu linemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. O ne of these may be a genetic abnormality of vascular smooth muscle cel ls. A similar situation may occur in humans.