Objective-High-density lipoprotein (HDL) cholesteryl esters (CE) are taken up by liver and adrenals selectively, ie, independent from particle internalization. Class B type I scavenger receptor (SR-BI) mediates this uptake in vitro. The role of SR-BI in HDL metabolism was explored in mice. Methods and Results-Mice with a mutation in the SR-BI gene (SR-BI KO) and wild-type (WT) littermates were used.Mutants had increased HDL cholesterol. HDL was labeled with 125 I (protein) and [ 3 H] (CE). After HDL injection, blood samples were drawn and finally the mice were euthanized. In WT, the plasma decay of HDL-associated [ 3 H] is faster compared with 125 I and this represents whole-body selective CE uptake. In SR-BI KO, the decay of both tracers is similar, yielding no selective CE removal. In WT liver and adrenals, uptake of [ 3 H] is higher than 125 I, showing selective uptake. In SR-BI KO, liver uptake of [ 3 H] and 125 I are similar, proposing no selective HDL CE uptake. In SR-BI KO adrenals, selective uptake is reduced; however, even in the absence of SR-BI, this uptake is detected using WT-HDL. Key Words: HDL Ⅲ SR-BI Ⅲ cholesterol Ⅲ liver Ⅲ receptor H igh-density lipoprotein (HDL) plays a critical role in cholesterol homeostasis. 1 HDL presumably removes cholesterol from peripheral tissues. 1,2 After esterification in plasma, HDL-associated cholesteryl esters (CE) are delivered to other lipoprotein fractions or to tissues. 1,2 One mechanism that mediates the delivery of HDL-associated CE to organs is the selective lipid uptake pathway. 3 In this process, HDL CE are internalized by cells independently from the uptake of the HDL particle. This selective lipid uptake appears to be important for the transport of cholesterol to steroidogenic tissues for hormone synthesis and to the liver. 3 In this central organ of lipid metabolism, HDL cholesterol is secreted into bile, used for bile acid synthesis, or packaged and secreted in newly synthesized lipoproteins. 2 This HDL-mediated transport of cholesterol from extrahepatic tissues to the liver is designated reverse cholesterol transport. 1 The class B type I scavenger receptor (SR-BI) is a cell surface HDL receptor that binds HDL. 4 In cultured cells, SR-BI mediates the selective HDL CE uptake. In rodents, SR-BI is most abundantly expressed in liver and steroidogenic tissues, 4 which are those tissues most actively engaged in selective lipid uptake in vivo. 3,5 In mice, hepatic overexpression of SR-BI reduces plasma HDL and increases biliary cholesterol. 6 In contrast, rodents with a targeted null mutation in the SR-BI gene have an increase in plasma HDL. 7 Taken together, evidence has been presented that SR-BI may be a physiologically relevant HDL receptor in vivo. Conclusions-SR-BIThe role of SR-BI in HDL metabolism was explored in mice with an attenuated expression of this receptor in liver and adrenals. 8 Studies using radiolabeled HDL showed that a 53% decrease in hepatic SR-BI expression is associated with a 47% reduction in HDL selective CE uptake by the liver...

Endothelins, nitric oxide, and oxygen-derived free radicals decisively regulate vascular tone. An imbalance in the biosynthesis of these substances in pathophysiologic conditions may trigger vasospasm and promote the development of atherosclerosis. Previous studies have shown that oxygen-derived free radicals can increase the synthesis of endothelin-1 in cultured endothelial cells. Interestingly, conditions of increased oxidative stress within smooth muscle cells as induced by angiotensin II infusion or hypercholesterolemia have been shown to be associated with increased autocrine synthesis of endothelin-1. Because endothelin-1 formed in smooth muscle cells can trigger hypersensitivity to vasoconstrictors, we tested whether oxidative stress per se may affect endothelin expression in vascular smooth muscle cells. Cultured human coronary artery smooth muscle cells were exposed to oxidative stress generated by the xanthine/xanthine oxidase reaction or by hydrogen peroxide. Preproendothelin-1 mRNA content was quantitated by means of quantitative polymerase chain reaction and endothelin-1 protein was measured by radioimmunoassay. Incubation with xanthine/xanthine oxidase significantly increased preproendothelin-1 mRNA synthesis, whereas GAPDH remained unchanged. Likewise, xanthine/xanthine oxidase also led to a dose-dependent increase of intracellular endothelin-1. The increase in ET-1 expression induced by xanthine/xanthine oxidase was significantly inhibited by superoxide dismutase but not by catalase. We conclude that oxygen-derived free radicals can stimulate the synthesis of endothelin-1 in endothelial and vascular smooth muscle cells by increasing preproendothelin-1 mRNA content and that this effect is mediated predominantly by superoxide anions. We therefore have identified a new mechanism in the interaction of oxidative stress and endothelin-1 expression in smooth muscle cells that may have important implications in diseases such as atherosclerosis and hypertension.