Editorial Commentary From Menace to Marvel High-Density Lipoprotein Prevents Endothelial Nitric Oxide Synthase Uncoupling in Diabetes Mellitus by Angiotensin II Type 1 Receptor Downregulation

Diabetes mellitus is a major risk factor for cardiovascular disease, and its prevalence is suspected to further increase in the coming years in the Western hemisphere and also in countries with emerging economies, like India, China, and Brazil. Together with the increasing prevalence of obesity and metabolic syndrome and the subsequent development of arterial hypertension, the epidemic of adiposity and diabetes mellitus may eat up most of the improvement of cardiovascular outcomes that we have seen within the last decades. 1 The risk of atherosclerosis is inversely related to circulating levels of high-density lipoprotein (HDL) cholesterol. Results from the Framingham Study demonstrated that this association is independent of low-density lipoprotein. Clinical trials using agents (eg, fibrates) that increase HDL have been shown to decrease cardiovascular event rates. On the other hand, therapy with the HDL-raising substance torcetrapib is associated with increased cardiovascular events, although the mechanism for this remains unclear and is probably independent of the effects on HDL cholesterol. 2 The classical function of HDL is the so called “reverse cholesterol transport” removing cholesterol from peripheral tissue and delivering it to the liver by binding of the major HDL apolipoprotein (apo), apoA-I, to the HDL receptor scavenger receptor B type I. Intra-arterial infusion of apoAI/phosphatidylcholine in hypercholesterolemic patients with normal HDL improves endothelial dysfunction, suggesting that HDL is a positive modulator of vascular NO bioavailability. Infusion of reconstituted HDL even leads to acute changes in human atherosclerotic plaque composition characterized by a reduction in lipid content within the atherosclerotic plaque. 3 With respect to endothelial dysfunction in the setting of diabetes mellitus, our group described first an uncoupled endothelial NO synthase (eNOS) in vascular tissue in an animal model of diabetes mellitus. 4 With these studies we