Abstract-It is well recognized that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. However, HDL has multiple additional endothelial and antithrombotic actions that may also afford cardiovascular protection. HDL promotes the production of the atheroprotective signaling molecule nitric oxide (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling. As importantly, there is evidence of a variety of mechanisms by which HDL is antithrombotic and thereby protective against arterial and venous thrombosis, including through the activation of prostacyclin synthesis. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of thrombosis. With further investigation and resulting greater depth of understanding, these mechanisms may be harnessed to provide new prophylactic and therapeutic strategies to combat atherosclerosis and thrombotic disorders. Key Words: atherosclerosis Ⅲ endothelial nitric oxide synthase Ⅲ endothelium Ⅲ HDL Ⅲ nitric oxide Ⅲ prostacyclin Ⅲ protein C Ⅲ thrombin Ⅲ thrombosis T he risk of atherosclerosis is inversely related to circulating levels of high-density lipoprotein cholesterol (HDL-C), 1,2 and the Framingham Heart Study demonstrated that the association is independent of low-density lipoprotein (LDL) cholesterol. 3,4 In addition, clinical trials with agents that increase HDL show that elevations in the lipoprotein decrease the incidence of cardiovascular events. 5-7 Furthermore, there is evidence that the risk for restenosis following a vascular intervention is inversely related to HDL. 8,9 HDL classically functions in reverse cholesterol transport (RCT), removing cholesterol from peripheral tissues and delivering it to the liver and to steroidogenic organs by binding of the major HDL apolipoprotein apolipoprotein A-I (apoA-I) to the highaffinity HDL receptor scavenger receptor B type I (SR-BI). 10,11 In mouse models of atherosclerosis, both apoA-I and SR-BI provide atheroprotection, 12,13 and the provision of apoA-I or HDL also attenuates neointima formation after artery injury in the context of experimental hypercholesterolemia. 14,15 The protective nature of HDL has been previously attributed to its role in RCT. However, the basis for Original

Background-Although dyslipoproteinemia is associated with arterial atherothrombosis, little is known about plasma lipoproteins in venous thrombosis patients. Methods and Results-We determined plasma lipoprotein subclass concentrations using nuclear magnetic resonance spectroscopy and antigenic levels of apolipoproteins AI and B in blood samples from 49 male venous thrombosis patients and matched controls aged Ͻ55 years. Venous thrombosis patients had significantly lower levels of HDL particles, large HDL particles, HDL cholesterol, and apolipoprotein AI and significantly higher levels of LDL particles and small LDL particles. The quartile-based odds ratios for decreased HDL particle and apolipoprotein AI levels in patients compared with controls were 6.5 and 6.0 (95% CI, 2.3 to 19 and 2.1 to 17), respectively. Odds ratios for apolipoprotein B/apolipoprotein AI ratio and LDL cholesterol/HDL cholesterol ratio were 6.3 and 2.7 (95% CI, 1.9 to 21 and 1.1 to 6.5), respectively. When polymorphisms in genes for hepatic lipase, endothelial lipase, and cholesteryl ester transfer protein were analyzed, patients differed significantly from controls in the allelic frequency for the TaqI B1/B2 polymorphism in cholesteryl ester transfer protein, consistent with the observed pattern of lower HDL and higher LDL. Conclusions-Venous thrombosis in men aged

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