THE EFFECT OF CHOLESTEROL REDUCTION ON THE ENDOTHELIAL FUNCTION AND PROGRESSION OF ATHEROSCLEROSIS IN WHHL RABBITS

In 3-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits the effect of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin was studied for 9 months and related to the endothelial function of the coronary arteries of isolated hearts and rings of the distal abdominal aorta. Oral administration of pravastatin in doses up to 40 mg/kg per day significantly decreased plasma cholesterol by 51% in comparison to untreated WHHL rabbits. Basal coronary flow and bradykinin-induced increase in coronary flow in Langendorff hearts of the pravastatin-treated animals were significantly greater than the flow in the control animals, whereas the metacholine-induced relaxation of abdominal aortic rings was not different and attenuated in comparison to New Zealand white rabbits. The incidence of atherosclerotic lesions in four main coronary arteries and the aorta was significantly lower in the pravastatin treated animals (25.0% and 52.8% respectively) than in untreated WHHL rabbits (34.1% and 80.0% respectively). The ml:an percentage of narrowing in the aorta was also significantly lower in the pravastatin-treated group (12.0%) than is the controls (25.2%). Significant correlations were found between the extent of atherosclerotic lesions and the bradykinin-induced increase in coronary flow versus plasma total cholesterol levels. Thus, in this model, long term cholesterol lowering treatment with pravastatin starting at an early age retards the progression of plaque formation and preserves the endothelium-dependent relaxation of the coronary arteries

The expression of type III hyperlipoproteinemia: involvement of lipolysis genes

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper- and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG) patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and type III HLP. The frequency of the rare allele of APOC3 3238 G > C and APOA5 - 1131 T > C (in linkage disequilibrium) was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs 5.8%, respectively, (P C polymorphism and LPL c.27 G > A mutation were higher in type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 - 1131 T > C, c.56 G > C and/or LPL c.27 G > A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7, 95% confidence interval = 1.8-7.5, P C/APOA5 - 1131 T > C polymorphism showed a more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type III HLP in APOE2/2