A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: Enhanced vasorelaxation and increased endothelial nitric oxide synthase expression (original) (raw)
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AJP: Endocrinology and Metabolism, 2009
Epidemiologic studies have shown that a low level of high-density lipoprotein (HDL) cholesterol is a risk factor for cardiovascular diseases. The purpose of this study was to determine the contribution of isolated low HDL cholesterol to endothelial function. Thirty-nine subjects with low HDL cholesterol who had no other cardiovascular risk factors were selected from the 5,417 participants from our population. We evaluated flow-mediated vasodilation (FMD) before and after 4 wk of treatment with the HMG-CoA reductase inhibitor pravastatin in 29 of the 39 subjects with isolated low HDL cholesterol. FMD was lower in the low-HDL-cholesterol group ( n = 29) than in the control group ( n = 29), whereas NTG-induced vasodilation was similar in the two groups. Pravastatin increased HDL cholesterol, urinary excretion of nitrite/nitrate, circulating levels of progenitor cells, and cell migration response to vascular endothelial growth factor in 15 subjects with low HDL cholesterol but not in 14...
Effects of high-density lipoprotein on endothelium-dependent vasorelaxation
Applied Physiology, Nutrition, and Metabolism, 2010
Studies using cultured endothelial cells have shown that high-density lipoprotein (HDL) positively modulates endothelial nitric oxide synthase (eNOS). The purpose of this study was to test the hypotheses that positive modulation of eNOS by HDL occurs in whole vessels and that it augments endothelium-dependent vasorelaxation. To test these hypotheses, brachial arteries were obtained from swine. Endothelium-dependent and endothelium-independent vasorelaxation were determined in vitro to assess the effects of acute administration of HDL (50 mgÁmL -1 ; n = 8) and chronic exposure to relatively high HDL concentration on vascular function (low HDL, 0.89 ± 0.02 mmolÁL -1 , n = 4; high HDL, 1.16 ± 0.05 mmolÁL -1 , n = 4; p < 0.005). Acute administration of HDL did not augment maximal endothelium-dependent vasorelaxation to bradykinin (BK) (no HDL, 82.6% ± 2.2%; HDL, 76.7% ± 3.5%; not significant (ns)). Similarly, maximal relaxation to BK was not enhanced by chronic exposure to high HDL concentrations. NO synthase (NOS) activity was also similar between groups (low HDL, 129.0 ± 19.2 countsÁh -1 Ámg -1 protein; high HDL, 113.9 ± 47.1 countsÁh -1 Ámg -1 ; ns). Consistent with NOS activity, the extent of eNOS phosphorylation at several sites was similar between low HDL and high HDL. Both apolipoprotein A-I (ApoA-I) and scavenger receptor class B type I (SR-BI) were associated with eNOS. Similar to cultured cell studies, this study demonstrates that both ApoA-I and SR-BI associate with eNOS in the vascular wall. Binding of ApoA-I and SR-BI to eNOS does not, however, result in modulation of either NO formation or endothelial function.
HDL and endothelial protection
British Journal of Pharmacology, 2013
High-density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apoA-I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity.
Atherosclerosis, 2010
Objective: Recent guidelines recommend more aggressive lipid-lowering in secondary prevention protocols. We examined whether this resulted in improved endothelial function. Methods: We studied saphenous vein specimens of patients undergoing surgical coronary revascularisation in 2007 and compared results with those of patients examined in 2003. Endothelium-dependent vasodilation was assessed by relaxation to calcium ionophore A23187, and vascular superoxide production by lucigenin enhanced chemiluminescence. Results: Statin dose increased from 26 ± 16 mg/d in 2003 to 37 ± 17 mg/d in 2007 (P < 0.001), and total (4.0 ± 0.9 mmol/L vs 4.8 ± 1.0 mmol/L) and LDL-cholesterol levels (2.0 ± 0.7 mmol/L vs 3.0 ± 0.9 mmol/L) were lower in 2007 compared to 2003 (P < 0.001; n = 90 each). Endothelium-dependent vasodilation was greater in 2007 (44 ± 15%) compared to 2003 (28 ± 12%; n = 36 each; P < 0.001). Vascular superoxide derived from endothelial NO synthase (eNOS) was lower in 2007 than in 2003 (reduction by N G -nitrol-arginine-methyl ester, 0.29 ± 0.21 nmol/(mg min) vs 0.09 ± 0.20 nmol/(mg min); P = 0.002). In linear regression analysis, LDL-cholesterol levels have been shown to be the major determinant of endothelial function in the combined 2003 and 2007 cohort.
2010
BACKGROUND: High-density lipoprotein (HDL)-raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. METHODS AND RESULTS: HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy ...
Circulation, 1998
Background-Impaired endothelium-dependent vasodilation is an early sign of atherosclerosis in hypercholesterolemic patients. We hypothesized that lipid-lowering therapy can improve endothelial function and that this effect is mainly mediated by increased bioavailability of nitric oxide (NO). Methods and Results-In a randomized, double-blind, placebo-controlled trial, we studied 29 patients (age, 50Ϯ12 years) with hypercholesterolemia (LDL cholesterol Ն160 mg/dL) randomly assigned to receive either fluvastatin (40 mg twice daily; 17 patients) or placebo (12 patients). Forearm blood flow was measured by plethysmography before and after 24 weeks of treatment. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of acetylcholine (ACh; 3, 12, 24, and 48 g/min) and basal NO synthesis rate by intra-arterial infusion of N G-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 mol/min). Simultaneous intra-arterial infusion of L-NMMA (4 mol/min) and ACh (12, 24, and 48 g/min) was used to test whether any increase in endothelium-dependent vasodilation after lipid-lowering therapy could be blocked by this NO synthase inhibitor. Endothelium-dependent vasodilation improved significantly after 24 weeks of lipid-lowering therapy compared with before therapy (ACh 24 g/min: 240Ϯ34% before versus 347Ϯ50% after therapy; PՅ0.01) and placebo (changes between after and before therapy with ACh 24 g/min: 108Ϯ39% for fluvastatin versus Ϫ26Ϯ32% for placebo; PՅ0.05). This improvement in endothelium-dependent vasodilation could be blocked by simultaneous administration of L-NMMA (ACh 24 g/min plus L-NMMA 4 mol/min: 170Ϯ69% before versus 219Ϯ47% after treatment; PϭNS). Conclusions-Lipid-lowering therapy with fluvastatin can improve disturbed endothelial function in hypercholesterolemic patients compared with placebo. This improvement is mediated by increased bioavailability of NO. (Circulation.
High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men
2011
Background—Hypercholesterolemia is a risk factor for atherosclerosis-causing endothelial dysfunction, an early event in the disease process. In contrast, high-density lipoprotein (HDL) cholesterol inversely correlates with morbidity and mortality representing a protective effect. Therefore, we investigated the effects of reconstituted HDL on endothelial function in hypercholesterolemic men. Methods and Results—Endothelium-dependent and -independent vasodilation to intraarterial acetylcholine and sodium nitroprusside (SNP), respectively,
15-Lipoxygenase-Mediated Modification of HDL3 Impairs eNOS Activation in Human Endothelial Cells
Lipids, 2014
Caveolae are cholesterol and glycosphingolipidsenriched microdomains of plasma membranes. Caveolin-1 represents the major structural protein of caveolae, that also contain receptors and molecules involved in signal transduction pathways. Caveolae are particularly abundant in endothelial cells, where they play important physiological and pathological roles in regulating endothelial cell functions. Several molecules with relevant functions in endothelial cells are localized in caveolae, including endothelial nitric oxide synthase (eNOS), which regulates the production of nitric oxide, and scavenger receptor class B type I (SR-BI), which plays a key role in the induction of eNOS activity mediated by high density lipoproteins (HDL). HDL have several atheroprotective functions, including a positive effect on endothelial cells, as it is a potent agonist of eNOS through the interaction with SR-BI. However, the oxidative modification of HDL may impair their protective role. In the present study we evaluated the effect of 15-lipoxygenasemediated modification of HDL 3 on the expression and/or activity of some proteins localized in endothelial caveolae and involved in the nitric oxide generation pathway. We found that after modification, HDL 3 failed to activate eNOS and to induce NO production, due to both a reduced ability to interact with its own receptor SR-BI and to a reduced expression of SR-BI in cells exposed to modified HDL. These findings suggest that modification of HDL may reduce its endothelial-protective role also by interfering with vasodilatory function of HDL. Keywords High density lipoprotein Á Endothelial cells Á 15-Lipoxygenase Á Caveolae Á Nitric oxide Abbreviations 15LO 15-Lipoxygenase ABCG1 ATP binding cassette transporter G1 CAV-1 Caveolin-1 eNOS Endothelial nitric oxide synthase HDL High density lipoprotein HUVEC Human umbilical vein endothelial cell(s) LOX-1 Lectin-like oxidized low-density lipoprotein receptor-1 MAPK Mitogen-activated protein kinase NO Nitric oxide S1P3
Metabolism, 2003
High-density lipoprotein-cholesterol (HDL-c) has a favorable influence on the endothelial function, but the mechanisms of this protective action are not fully understood. We studied lipid parameters, soluble adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule [ICAM-1], E-selectin) oxidized low-density lipoproteins (LDL), and brachial-artery flow-mediated vasodilation (FMV) in 184 hyperlipemic patients (90 men, age 54 +/- 10 years, waist/hip circumference ratio 0.89 +/- 0.07, LDL-cholesterol [LDL-c] 4.9 +/- 1.3 mmol/L, triglycerides 1.8 +/- 0.9 mmol/L, HDL-c 1.3 +/- 0.5 mmol/L) after excluding those with current smoking, diabetes, hypertension, and vascular diseases. Patients were divided into 2 groups on the basis of HDL-c levels: &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 1.03 mmol/L (n = 53) v &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 1.03 mmol/L (n = 131). Patients with low HDL-c showed significantly lower LDL-c (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05), higher triglycerides (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001), higher body mass index (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.02), lower FMV (3.7% +/- 2.0% v 4.9% +/- 3.4%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.002), higher VCAM-1 (1,195 +/- 395 ng/mL v 984 +/- 303 ng/mL, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.01), and higher ICAM-1 (406 +/- 78 ng/mL v 364 +/- 68 ng/mL, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.01). E-selectin and oxidized LDL showed no significant differences. In a multivariate age, oxidized LDL and brachial artery diameter predicted a lower FMV, while HDL-c was an independent predictor of a greater FMV (P =.003). Increasing levels of VCAM-1 and ICAM-1 were predicted by lower HDL-c, while higher oxidized LDL predicted higher VCAM-1 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05). Our data suggest that in hyperlipemic subjects free of cardiovascular disease low HDL-c negatively modulates endothelial function through a lack of oxidation inhibition and a concomitant overexpression of adhesion molecules.