High Density Lipoprotein Binding to Scavenger Receptor, Class B, Type I Activates Endothelial Nitric-oxide Synthase in a Ceramide-dependent Manner

Li, Xiang-An; Titlow, William B.; Jackson, Brian A.; Giltiay, Nathalia; Nikolova‐Karakashian, Mariana; Uittenbogaard, Annette; Smart, Elizabeth

doi:10.1074/jbc.m110985200

Cited by 158 publications

(126 citation statements)

References 28 publications

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“…One of the potential cardioprotective actions of HDL is thought to be its activation of eNOS leading to production of NO (16,24,27,36). Similarly, the cardioprotective actions of estrogen include its ability to stimulate eNOS activity/NO production.…”

Section: Discussionmentioning

confidence: 99%

“…In each experiment, cytosolic calcium was measured simultaneously in 12-14 fura-2-loaded cells by using a dualexcitation spectrofluorometric system (Zeiss AttoFluor Ratio Vision Workstation; Atto Instruments, Rockville, MD) (24). Before analysis, the cells were rinsed three times with PBS and loaded with 5 M fura-2 AM for 10 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Although the data clearly show that diabetic HDL prevents eNOS-calmodulin interaction, it is possible that diabetic HDL has other, noncalmodulin-related, effects on eNOS. To test this possibility, we stimulated eNOS with ceramide, which is independent of calcium-calmodulin but still requires other eNOS cofactors (24). HME cells were then incubated with 0.75 Ci/ml of [ 3 H]arginine to label the intracellular arginine pool.…”

Section: Diabetic Hdl Does Not Alter the Expression Of Enos Acetylchmentioning

confidence: 99%

“…For instance, diabetic persons often have poor peripheral circulation, which leads to ischemic injury, impaired wound healing, and impaired vision, all of which involve altered endothelial cell function that relates to endothelial nitric oxide (NO) synthase (eNOS) and the generation of NO (2,21). Several studies have shown that HDL acting through its receptor, SR-BI, can stimulate eNOS to produce NO (4,16,24,36). Interestingly, both calcium-dependent and calcium-independent mechanisms have been shown to account for HDL-mediated NO generation.…”

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confidence: 99%

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Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin

White

Guerin

Swanson

et al. 2008

American Journal of Physiology-Cell Physiology

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Smart EJ. Diabetic HDL-associated myristic acid inhibits acetylcholineinduced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin. Am J Physiol Cell Physiol 294: C295-C305, 2008. First published October 31, 2007 doi:10.1152/ajpcell.00042.2007.-In the current study, we examined whether diabetes affected the ability of HDL to stimulate nitric oxide (NO) production. Using HDL isolated from both diabetic humans and diabetic mouse models, we found that female HDL no longer induced NO synthesis, despite containing equivalent amounts of estrogen as nondiabetic controls. Furthermore, HDL isolated from diabetic females and males prevented acetylcholine-induced stimulation of NO generation. Analyses of both the human and mouse diabetic HDL particles showed that the HDLs contained increased levels of myristic acid. To determine whether myristic acid associated with HDL particles was responsible for the decrease in NO generation, myristic acid was added to HDL isolated from nondiabetic humans and mice. Myristic acid-associated HDL inhibited the generation of NO in a dose-dependent manner. Importantly, diabetic HDL did not alter the levels of endothelial NO synthase or acetylcholine receptors associated with the cells. Surprisingly, diabetic HDL inhibited ionomycin-induced stimulation of NO production without affecting ionomycin-induced increases in intracellular calcium. Further analysis indicated that diabetic HDL prevented calmodulin from interacting with endothelial NO synthase (eNOS) but did not affect the activation of calmodulin kinase or calcium-independent mechanisms for stimulating eNOS. These studies are the first to show that a specific fatty acid associated with HDL inhibits the stimulation of NO generation. These findings have important implications regarding cardiovascular disease in diabetic patients. fatty acid; lipoprotein; diabetes; signaling CARDIOVASCULAR DISEASES are influenced by both genetic and environmental factors that can negatively or positively influence the development and progression of cardiovascular diseases, such as plasma levels of LDL and HDL (25,26). High plasma levels of LDL promote the accumulation of cholesterol in vessel wall macrophages and the formation of atherosclerotic plaque (3,

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Diabetic Hdl Does Not Alter the Expression Of Enos Acetylchmentioning

confidence: 99%

mentioning

confidence: 99%

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Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin

White

Guerin

Swanson

et al. 2008

American Journal of Physiology-Cell Physiology

Self Cite

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“…Owing to its established paraoxonase and platelet-activating factor hydrolase activities, HDL has antioxidant properties that help mitigating vascular oxidative stress and prevent subsequent impairment of NO release. 42 Other mechanisms for the increased NO bioavailability by HDL include direct activation of endothelial NO synthase (eNOS) via interaction with scavenger receptor class B type I (SR-BI) receptor, 43 enhancement of intracellular ceramide levels, 43 and inhibition of oxidized LDL-induced disruption of plasma membrane caveola, thereby increasing the subcellular localization and activation of eNOS. 44 Additionally, HDL has been shown to inhibit apoptosis and enhance migration and re-endothelialization of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of niacin on endothelial function: A systematic review and meta-analysis of randomized controlled trials

Sahebkar

2014

Vasc Med

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Endothelial dysfunction is an independent predictor of incident atherosclerotic cardiovascular disease (ACVD). Niacin possesses high-density lipoprotein (HDL)-elevating, antioxidant and anti-inflammatory properties, all potentially contributing to the amelioration of endothelial function. However, controversies exist among trials reporting the effects of niacin on endothelium-dependent flow-mediated dilation (FMD) as a reliable surrogate of endothelial function. The objective of this study was to assess the effect of niacin on brachial artery FMD using a meta-analysis of available evidence. MEDLINE and Scopus databases were searched for randomized controlled trials investigating the impact of niacin therapy on brachial artery FMD. Meta-analysis of eligible studies was conducted using a random-effects model. Pooled effects were measured by weighted mean difference (WMD) and 95% confidence intervals (CIs). Quality assessment, and subgroup, meta-regression and sensitivity analyses were conducted using standard methods. Among 596 citations, 19 full-text articles were read and seven were found to be eligible for inclusion. Eligible studies involved 441 subjects comprising 228 in the niacin and 213 in the control groups. Niacin therapy significantly improved FMD (WMD: 1.98%; 95% CI: 0.91-3.05%; p = 0.0003) and this effect was robust in the sensitivity analysis. The effect size was greater in the subgroup of studies administering higher doses of niacin (≥ 2000 mg/day) as well as those studies administering niacin for primary prevention of ACVD. Metaregression indicated no association between niacin-induced changes in FMD and changes in plasma HDL-cholesterol, lowdensity lipoprotein-cholesterol or triglycerides. None of the included studies could find any significant effect of niacin on nitroglycerin-mediated dilation. In conclusion, treatment with niacin improves endothelial function.

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High‐Density Lipoprotein and Atheroprotection

Krause¹,

Homan²,

Newton³

2007

Endothelial Dysfunctions in Vascular Disease

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High Density Lipoprotein Binding to Scavenger Receptor, Class B, Type I Activates Endothelial Nitric-oxide Synthase in a Ceramide-dependent Manner

Cited by 158 publications

References 28 publications

Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin

Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin

Effect of niacin on endothelial function: A systematic review and meta-analysis of randomized controlled trials

High‐Density Lipoprotein and Atheroprotection

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