'Good' cholesterol function as important as its levels

High levels of "good" cholesterol (HDL cholesterol) are associated with a decreased risk of coronary artery disease (CAD) - a disease of the major arterial blood vessels that is one of the major causes of heart attack and stroke. This suggests that therapeutics that increase HDL levels could be clinically useful.

However, such therapies have not yielded clear-cut decreases in disease, indicating that the beneficial effects of HDL are likely not related simply to its abundance. More evidence to support this notion has now been provided by a team of researchers, led by Ulf Landmesser, at the University of Zurich, Switzerland, who found that HDL from patients with (CAD) had different effects on cells lining blood vessels than did HDL from healthy individuals. In particular, the HDL from patients with CAD was found to lack anti-inflammatory effects on blood vessel–lining cells and could not stimulate repair of the blood vessel lining.

As noted by the team and, in an accompanying commentary, Philip Shaul and Chieko Mineo, at The University of Texas Southwestern Medical Center, Dallas, these data indicate that if the protective potential of HDL is to be harnessed, its biological functions as well as its abundance must be considered.

Furthermore, in patients with CAD and low levels of LDL cholesterol receiving statin treatment, low HDL cholesterol levels were predictive of an elevated risk of major cardiovascular events.

Notably, besides promotion of cholesterol efflux from macrophage foam cells, HDL has been found to exert several important endothelial antiatherogenic effects. In particular, several recent studies have indicated that HDL stimulates endothelial cell NO production and promotes endothelial repair mechanisms. These protective effects of HDL on eNOS and endothelial repair are, at least in part, mediated via endothelial scavenger receptor B, type I (SR-BI) and involve cholesterol efflux and the adaptor molecule PDZK1. Moreover, by binding to SR-BI, HDL has been reported to activate eNOS via stimulation of the phosphorylation of eNOS at Ser1177, induced via PI3K and Akt kinase. In addition, HDL has been reported to partly stimulate eNOS-activating phosphorylation at Ser1177 and endothelial NO production via endothelial sphingosine-1-phosphate receptor 3 (S1P3). Moreover, recent studies in mice have demonstrated that HDL protects against dietary cholesterol–induced endothelial dysfunction by promoting cholesterol efflux and release of 7-ketocholesterol via the endothelial ABCG1 transporter, and reduced hypercholesterolemia-induced interaction of caveolin-1 with eNOS. In humans with hypercholesterolemia or with isolated low HDL levels due to heterozygous ABCA1 gene mutations, administration of reconstituted HDL has been observed to normalize impaired endothelium-dependent, NO-mediated vasodilation. These endothelial-protective effects of HDL are thought to contribute importantly to its antiatherogenic functions. Indeed, endothelial dysfunction, in particular reduced endothelial NO bioavailability, is considered to play a key role in the initiation and progression of atherosclerosis and its clinical complications .