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 .
Based on epidemiological studies and observations of potential atheroprotective properties of HDL, HDL-raising interventions are currently being intensely evaluated as a novel therapeutic strategy in patients with CAD. The adverse effects of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib on cardiovascular outcome, which were observed despite a substantial increase in HDL levels, have suggested that a better understanding of the vascular effects of HDL from patients with CAD is urgently required.
Indeed, the capacity of HDL to mediate cholesterol efflux from lipid-laden macrophages has been observed to be impaired after substantial oxidative modification of HDL by myeloperoxidase or malondialdehyde, a lipid peroxidation product, as observed in atherosclerotic plaques. In addition, the capacity of HDL to prevent the proinflammatory effects of LDL, i.e., LDL-induced monocyte chemotactic activity (34), was impaired in patients with CAD. Furthermore, the effects of HDL on endothelial NO bioavailability can be highly variable, as observed in patients with type 2 diabetes or antiphospholipid syndrome (APS); however, the underlying mechanisms remain to be determined. Interestingly, we have observed that reduced serum activity of paraoxonase 1 (PON1), an HDL-associated enzyme, was related to endothelial dysfunction in patients with APS; however, whether PON1 plays a causal role in the effects of HDL on endothelial NO production remains unknown. Moreover, as described above, patients with CAD represent a major target population for HDL-raising therapies, and whether the effects of HDL from these patients on endothelial NO production and eNOS-dependent atheroprotective pathways are altered remains to be determined.
The present study was therefore designed to compare the effects of HDL from patients with stable CAD (sCAD) or acute coronary syndrome (ACS) with those of HDL from healthy subjects on eNOS-activating or -inhibiting pathways and endothelial NO production, and to investigate the role of HDL-induced NO production for the capacity of HDL to inhibit endothelial antiinflammatory activation and to stimulate endothelial repair. In particular, we focused on the characterization of the mechanisms underlying altered effects of HDL from patients with CAD on endothelial cell NO production and eNOS-dependent pathways.
Low HDL cholesterol levels are associated with an increased risk of CAD and major cardiovascular events. Besides promotion of cholesterol efflux from macrophage foam cells, stimulation of eNOS-dependent NO production and mediation of endothelial repair mechanisms, as well as antiinflammatory effects, have been proposed as potential antiatherogenic properties of HDL. HDL-raising therapies are currently being intensely evaluated for prevention and treatment of CAD.
The present study demonstrates that HDL from patients with either sCAD or an ACS - in contrast to HDL from healthy subjects - fails to stimulate endothelial NO production. Of note, reduced endothelial NO bioavailability is thought to contribute to development and progression of atherosclerosis, at least in part by promoting endothelial inflammatory activation (22, 23). In this respect, the inability of HDL from patients with CAD to stimulate endothelial NO production, as observed in the present study, suggests a loss of this potential antiatherogenic property of HDL.
Our findings suggest that stimulation of endothelial NO production is important for HDL’s ability to inhibit inflammatory activation of endothelial cells, i.e., to reduce NF-κB activity, VCAM-1 expression, and monocyte adhesion, which are thought to play a role in the development and progression of atherosclerosis. In addition, HDL-induced stimulation of endothelial repair was not observed in eNOS-deficient mice, suggesting a role of eNOS in this process. We therefore examined the mechanisms underlying alterations of these potential endothelial-atheroprotective effects of HDL in patients with CAD.
TITLE: Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
University of Zurich, Zurich, Switzerland.
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TITLE: PON-dering differences in HDL function in coronary artery disease
Philip W. Shaul
The University of Texas Southwestern Medical Center, Dallas, Texas, USA.