Prospective population studies in the primary prevention setting have shown that reduced plasma levels of
HDL cholesterol are associated with an increased risk of
coronary disease and
myocardial infarction. Experimental and translational studies have further revealed several potential anti-atherogenic effects of HDL, including protective effects on endothelial cell functions. HDL has been suggested to protect endothelial cell functions by prevention of oxidation of
LDL and its adverse endothelial effects. Moreover, HDL from healthy subjects can directly stimulate endothelial cell production of
nitric oxide and anti-inflammatory, anti-apoptotic, and anti-thrombotic effects as well as endothelial repair processes. However, several recent clinical trials using
HDL cholesterol-raising agents, such as
torcetrapib,
dalcetrapib, and
niacin, did not demonstrate a significant reduction of cardiovascular events in patients with
coronary disease. Of note, growing evidence suggests that the vascular effects of HDL can be highly heterogeneous and vasoprotective properties of HDL are altered in patients with
coronary disease. Characterization of underlying mechanisms and understanding of the clinical relevance of this "HDL dysfunction" is currently an active field of cardiovascular research. Notably, in some recent studies no clear association of higher
HDL cholesterol levels with a reduced risk of cardiovascular events was observed in patients with already established
coronary disease. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted
therapies. In this review, we will address different effects of HDL on endothelial cell functions potentially relevant to atherosclerotic
vascular disease and explore molecular mechanisms leading to "dysfunctional HDL".