Effect of High-Density Lipoproteins on Experimental Atherosclerosis

Abstract

Epidemiologic studies and cell culture studies have given information tending to establish an inverse relationship between HDL-cholesterol levels and incidence of coronary artery disease (CAD). It was suggested that HDL exerts its effect by enhancing the rate of cholesterol removal from arterial wall. However, no interventional prospective studies designed to test the preventive effect of raised levels of HDL on atherosclerosis have been reported. Our study is a preliminary approach to exploring the potential antiatherogenic effect of HDL in vivo. We have examined the effect of intravenous injections of HDL during the induction and regression of experimental atherosclerosis. Four homogeneous groups of New Zealand white rabbits were fed a cholesterol-rich diet (0.5%) for 60 days at a daily intake of 140 g. The HDL were obtained by ultracentrifugation of normal rabbit plasma (density range 1.063-1.25 g/ml, HDL + VHDL). All groups were studied simultaneously. A weekly injection of HDL (50 mg protein; 12.2 mg cholesterol) or its vehicle was administered to each group as follows. Group I (N = 10) received HDL simultaneously with the atherogenic diet. Group II (N = 10) was the placebo (atherosclerotic control group). Group III (N = 7) received HDL once the atherosclerosis was established (after 2 months of induction by the same cholesterol-rich diet). Group IV (N = 5) received HDL vehicle and was the placebo for group III. The last two groups resumed standard rabbit chow during the regression period, which lasted 1 month. Plasma lipid levels followed a similar profile in all the groups throughout the study. At sacrifice, group I and II showed total cholesterol (Cho) 1585 ± 172 and 1546 + 109, HDL-cho 63 ± 6 and 59 ± 6, and triglycerides (TGL) 66 ± 8 and 62 ± 9 mg/dl, respectively. Groups III and IV, after resuming normal rabbit chow for 1 month, presented values of cho 265 ± 16 and 291 ± 63, HDL-cho 17 ± 2 and 18 ± 3, and TGL 56 ± 7 and 58 ± 4 mg/dl, respectively. No significant difference was observed in these levels between groups I and II and between groups III and IV. At the completion of the study, the aortas were removed, and the atherosclerotic lesions were visualized by Sudan IV staining and blindly evaluated by three different observers using computerized planimetry. The percentage of aortic involvement with fatty streaks were: group I 13 ± 5, group II 42 ± 16, group III 41 ± 19, and group IV 40 ± 6. Group I (atherosclerosis-induction, HDL-treated group) showed a significantly lower aortic atherosclerotic involvement than group II (AT-induction, palcebo) (P < 0.001). The regression groups did not show any difference in aortic atherosclerotic involvement after treatment with HDL. Homologous HDL injections can markedly inhibit fatty streak formation during experimental atherosclerosis. They have been shown to be less effective in reducing fatty streak involvement of aorta once atherosclerosis has taken place. The results suggest that the antiatherogenic role of HDL might be mediated through a competitive inhibition with the low-density lipoproteins (LDL) for binding to the LDL receptors rather than an enhanced reverse cholesterol transport from the aortic wall