A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: Enhanced vasorelaxation and increased endothelial nitric oxide synthase expression

Abstract

Background: Low levels of high-density lipoprotein (HDL) cholesterol increase the risk of coronary artery disease (CAD), and recent clinical studies suggest that interventions in low-HDL patients are beneficial. The purpose of this study was to examine the effect of increased HDL levels on endothelium-dependent vasodilation. Methods: We studied patients with CAD with a low-density lipoprotein (LDL) level of <100 mg/dL. Patients with an HDL level of <36 mg/dL were treated with niacin (n = 11), and patients with an HDL level of >36 mg/dL were followed as controls (n = 10). Baseline and 3-month follow-up studies of flow-mediated dilation (FMD) and blood lipid levels were obtained. Results: HDL levels increased from 30.1 ± 1.2 to 40.5 ± 1.2 mg/dL in the niacin-treated patients (P < .001) but remained unchanged in the control patients. At baseline, FMD was impaired in both the treated (6.5% ± 1%) and the control (7.3% ± 1%) patients compared with 10 healthy subjects (16% ± 2%, P < .01). After 3 months, FMD improved in the niacin-treated patients (11.8% ± 1%, P = .001) but remained unchanged in the control patients (6.2% ± 1%). Exposure of cultured human vascular endothelial cells to HDL in vitro enhanced expression of endothelial nitric oxide synthase (eNOS), as shown by immunoblotting. Conclusions:In patients with CAD and well-controlled LDL levels, elevation of HDL with niacin improves endothelial function. HDL increases eNOS protein expression in cultured vascular endothelial cells. Taken together, these observations suggest that HDL-mediated increases in eNOS expression may contribute to the observed enhancement in vasorelaxation and thus support a previously unrecognized mechanism for the beneficial cardiovascular effects of HDL.

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

“…However, in previous studies performed in type 2 diabetic patients or insulin-resistant subjects no correlation could be found between the activity of these two enzymes and the decreased antioxidant properties of HDL [10,26,27]. Therefore, it is unlikely that we could have explained the decreased vasorelaxant effect of HDL from type 2 diabetic patients by a decrease in PAF-AH and lecithin cholesterol acyltransferase activities.…”

“…Secondly, the binding of HDL to the lysophospholipid receptor S1P 3 activates Ca 2+ -calmodulin-dependent kinases and Akt with consecutive activation of eNOS [25]. Finally, HDL can increase the expression of the gene encoding eNOS [26].…”

Dyslipidaemia and microvascular disease in the retina

“…13 However, our data are consistent with findings from two previous studies that brachial arterial diameters were wider in persons with lower HDL cholesterol than in those with higher HDL cholesterol levels. 36,37 Explanation of such findings is not readily available. Atherosclerosis is traditionally described as a gradual ingrowth of plaques within the vessel lumen, leading to narrowed vessel diameter.…”

Linking erectile dysfunction and coronary artery disease

“…15 There are emerging data suggesting that high-density lipoprotein may independently and favorably effect endothelial function. [59][60][61] The effects of hypertriglyceridemia, however, are less clear.…”