Role of 3β-Hydroxysteroid-Δ24 Reductase in Mediating Antiinflammatory Effects of High-Density Lipoproteins in Endothelial Cells

McGrath, Kristine; Li, X.H.; Puranik, Rajesh; Liong, Emily C.; Tan, Joanne; Dy, Veronica; Bartolo, Belinda A. Di; Barter, Philip J.; Rye, Kerry Anne; Heather, Alison K.

doi:10.1161/atvbaha.109.184663

Cited by 84 publications

(73 citation statements)

References 28 publications

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“…HDL3 was found to impede TNFα-induced upregulation of VCAM-1 and E-selectin expression in human umbilical vein endothelial cells by antagonizing activation of sphingosine kinase and subsequent intracellular formation of S1P (Xia et al 1999). Furthermore, it has been documented that in cultured endothelial cells, incubation with HDLs prevented NF-κβ activation, movement of p65 to the nucleus, and expression of NF-κβ target genes in response to TNFα (Xia et al 1999;Park et al 2003;Kimura et al 2006;McGrath et al 2009). The basal molecular mechanisms of the beneficial effects of HDL on endothelial inflammation are dependent on an increase in the expression of 3β-hydroxysteroid-Δ24 reductase that results in activation of PI3K and downstream activation of eNOS and heme oxygenase-1 (HO-1) (McGrath et al 2009;Wu et al 2013).…”

Section: Suppression Of Monocyte Extravasationmentioning

confidence: 95%

“…Furthermore, it has been documented that in cultured endothelial cells, incubation with HDLs prevented NF-κβ activation, movement of p65 to the nucleus, and expression of NF-κβ target genes in response to TNFα (Xia et al 1999;Park et al 2003;Kimura et al 2006;McGrath et al 2009). The basal molecular mechanisms of the beneficial effects of HDL on endothelial inflammation are dependent on an increase in the expression of 3β-hydroxysteroid-Δ24 reductase that results in activation of PI3K and downstream activation of eNOS and heme oxygenase-1 (HO-1) (McGrath et al 2009;Wu et al 2013). Specific knockdown of SR-BI or S1P1 receptor by treatment of human endothelial cells with small interfering RNAs against SR-BI and PDZK1 or S1P1, respectively, markedly reduced the ability of HDLs to inhibit VCAM-1 expression and NF-κβ activation (Kimura et al 2006;Wu et al 2013), suggesting that both receptors may be critical for the anti-inflammatory endothelial actions of HDLs.…”

Section: Suppression Of Monocyte Extravasationmentioning

confidence: 99%

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HDL and Atherothrombotic Vascular Disease

Annema

Eckardstein

Kovanen

2014

High Density Lipoproteins

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High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.

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Section: Suppression Of Monocyte Extravasationmentioning

confidence: 95%

Section: Suppression Of Monocyte Extravasationmentioning

confidence: 99%

HDL and Atherothrombotic Vascular Disease

Annema

Eckardstein

Kovanen

2014

High Density Lipoproteins

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“…One such protein that is induced both in vitro ( 87 ) and in vivo ( 88 ) by rHDLs is the antioxidant protein 3 ␤ -hydroxysteroid-⌬ 24 reductase (also known as 24-dehydrocholesterol reductase or DHCR24). Silencing DHCR24 expression in endothelial cells not only increases nuclear factor B cells (NF-B) activation and VCAM-1 protein levels in both nonactivated and TNF-␣ -activated endothelial cells, but it is also associated with a loss of the anti-infl ammatory effects of rHDLs ( 87 ). The rHDL-induced expression of DHCR24 in cultured endothelial cells is dependent on SR-B1, but not on ABCA1 or ABCG1 ( 87 ).…”

Section: Roles Of Specifi C Hdl Constituents and Subpopulations As Mementioning

confidence: 99%

Cardioprotective functions of HDLs

Rye

Barter

2014

Journal of Lipid Research

243

171

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This article is available online at http://www.jlr.org inverse predictors of the risk of having a cardiovascular event ( 1-5 ); moreover, a low concentration of HDL cholesterol remains predictive of increased cardiovascular risk, even when low density lipoprotein (LDL) cholesterol has been reduced to very low levels by treatment with statins ( 6 ); ii ) HDLs have several well-documented functions with the potential to protect against cardiovascular disease ( 7,8 ); iii ) interventions that increase the concentration of HDLs inhibit the development and progression of atherosclerosis in several animal models ( 9-12 ); and iv ) in "proofof-concept" studies in humans, intravenous infusions of reconstituted HDLs (rHDLs) consisting of apoA-I complexed with phospholipids promote regression of coronary atheroma as assessed by intravascular ultrasound ( 13,14 ).However, interventions that increase the concentration of HDL cholesterol in humans have not yet been shown to translate into a reduction in clinical cardiovascular events. Indeed, recent human clinical trials investigating the effects of raising the level of HDL cholesterol by treatment with cholesteryl ester transfer protein (CETP) inhibitors or with niacin failed to demonstrate any clinical cardiovascular benefi t ( 15-17 ) (http://www.thrivestudy. org), and in one case, the treatment caused harm ( 15 ). A reasonable assumption that has been made from these studies is that the cholesterol content of HDLs is not the factor that protects. Thus, if HDLs do have direct cardioprotective properties, it follows from the human population studies that, while the concentration of HDL cholesterol is generally an excellent marker of the HDL functions that do protect, it does not invariably refl ect their cardioprotective functions. This is consistent with the fi nding in a recent Mendelian randomization study that some genetic mechanisms that raise the concentration of HDL cholesterol appear not to lower the risk of myocardial infarction ( 18 ). The authors of this analysis concluded that, while The proposition that high density lipoproteins (HDLs) protect against the development of cardiovascular diseases is based on a number of robust and consistent observations: i ) numerous human population studies have shown that the plasma concentrations of both HDL cholesterol and the major HDL apolipoprotein, apoA-I, are independent, Abbreviations: CETP, cholesteryl ester transfer protein; HO-1, heme oxygenase-1; PON-1, paraoxonase-1; rHDL, reconstituted HDL; SR-B1, scavenger receptor-B1; VCAM-1, vascular cell adhesion molecule-1.

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“…Studies on endothelial cells have shown that HDL are able to inhibit the cytokineinduced expression of cell adhesion molecules (Calabresi et al 1997;Cockerill et al 1995), but the precise mechanism responsible for this effect has not been fully elucidated to date (Barter et al 2002). Different studies have shown an HDL-mediated inhibition of sphingosine kinase activity and NF-kB nuclear translocation and an increased expression of heme-oxygenase 1 mediated by SR-BI (McGrath et al 2009;Xia et al 1999). HDL was also shown to inhibit the production of proinflammatory cytokines, as interleukin-6 and chemokines (Gomaraschi et al 2005).…”

Section: Effect On Hdl Ability To Preserve Endothelial Cell Homeostasismentioning

confidence: 99%