Abstract
Murine models of atherosclerosis is increasingly used for the studies of atherosclerosis. 1) We compared atherosclerosis of LDLR-/-, apo E-/-or LDLR-/-;apo E-/- mice in light of their lipoprotein profiles. The mice were fed a nomlal chow, and sacrified at age 12 months. Aortic lesions were visualized by staining with Sudan IV. Wild type mice had no lesins. The lesions of the LDLR-/- mice were restricted to the aortic arch, couprising only 5% of the total surface area of the aorta. On the other hand, the lesions of the apo E-/- mice were more extensive and involved 30% of the total surface area. The aortic arches were totally diseased with skipping lesions in other parts of the aorta. Lesions in the LDLR-/-;apo E-/- mice deVeloped advanced further. Most of he luminal surface of he aorta (80%) was covered with lesion coalescence. Mean plasma cholesterol levels of the wild type, LDLR-/-, apo E-/-, and LDLR-/-;apo E-/- mice were 101, 388, 543, and 578mg/dl, respectively. Thus, the differences in atherosclerotic progression between apo E-/- and LDLR-/-;apo E-/- mice were not attributable to the differences in plasua cholesterol levels but to a coubined elevation of LDL and reunants. In conclusion, LDL accelerates atherosclerosis synergis. tically with reunant lipoproteins. LDLR-/-;apo E-/- mice may serve as a model of rampant atherosclerosis. 2) Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Conflicting results have been reported concerning its role in atherogenesis. To determine the effects of the overexpressed LPL on diet-induced atherosclerosis, we have generated low density lipoprotein receptor (LDLR) knockout mice which overexpressed huuan LPL transgene (LPL/LDLRKO) and compared their plasma lipoproteins and atherosclerosis with those in non-expressing LDLR-knockout mice (LDLRKO). On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 vs 236mg/dl) andmodest decrease in mean cholesterol levels (300 vs 386mg/dl) as compared with LDLRKO mice. Larger lipoprotein particles of LDL/LDL were selectively reduced in LPL/LDLRKO mice. On an atherogenic diet, both mice exhibited severe hypercholesterolemia. But, mean plasua cholesterol levels in LPL/LDLRKO mice were still suppressed as coupared with that in LDLRKO mice (1, 357 vs 2, 187mg/dl). Marked reduction in a larger subfraction of IDL/LDL, which conceivably corresponds to remnant lipoproteins, was observed in the LPL/LDLRKO mice. LDLKO mice developed severe fatty streak lesions in the aortic sinus after feeding with the atherogenic diet for 8 weeks. In contrast, mean lesion area in the LPL/LDLRKO uice was 18-fold smaller than than that in LDLRKO mice. We suggest that the altered lipoprotein profile, in particular, reduced level of remnant lipoproteins is mainly responsible for the protection by LPL against atherosclerosis.
