High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase

Atherosclerosis is the primary cause of cardiovascular disease, and the ris k for atherosclerosis is inversely proportional to circulating levels of hi gh-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL is atheroprotective are complex and not well understood(1,2), Here we s how that HDL stimulates endothelial nitric oxide synthase (eNOS) in culture d endothelial cells. In contrast, eNOS is not activated by purified forms o f the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipopr otein. Heterologous expression experiments in Chinese hamster ovary cells r eveal that scavenger receptor-BI (SR-BI) mediates the effects of HDL on the enzyme. HDL activation of eNOS is demonstrable in isolated endothelial-cel l caveolae where SR-BI and eNOS are colocalized, and the response in isolat ed plasma membranes is blocked by antibodies to ApoA-I and SR-BI, but not b y antibody to ApoA-II. HDL also enhances endothelium- and nitric-oxide-depe ndent relaxation in aortae from wild-type mice, but not in aortae from homo zygous null SR-BI knockout mice. Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-o xide production might be critical to the atheroprotective properties of HDL and ApoA-I.