Gene transfer and hepatic overexpression of the HDL receptor SR-BI reducesatherosclerosis in the cholesterol-fed LDL receptor-deficient mouse

HDL cholesterol levels in humans are inversely correlated with the risk of atherosclerosis. The class B scavenger receptor type I (SR-BI) is the first molecularly well-defined HDL receptor, and hepatic overexpression of SR-BI in normal mice has been shown to result in decreased plasma HDL cholestero l levels. To determine whether SR-BI overexpression is proatherogenic or is protective against atherosclerosis, LDL receptor-deficient mice were place d on a high-fat/high-cholesterol diet for 2 or 12 weeks to induce atheroscl erotic lesions of different stages and then were injected with a recombinan t adenovirus encoding murine SR-BI. Transient hepatic overexpression of SR- BI in mice with both early and advanced lesions significantly decreased ath erosclerosis. SR-BI expression was associated with markedly decreased HDL c holesterol and either unchanged or only modestly reduced non-HDL cholestero l levels; in all experiments, the mean HDL cholesterol levels were signific antly correlated with atherosclerotic lesion size. These data suggest that interventions that promote HDL cholesterol transport and lower plasma HDL c holesterol levels can suppress atherosclerosis, even when initiated after s ignificant lesion development. Thus, stimulation of hepatic SR-BI activity may provide a novel target for therapeutic intervention in atherosclerotic cardiovascular disease.