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Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.

Besler C, Lüscher TF, Landmesser U - EMBO Mol Med (2012)

Bottom Line: Studies in gene-targeted mice, however, have also indicated that increasing HDL-cholesterol plasma levels can either limit (e.g. apolipoprotein A-I) or accelerate (e.g. Scavenger receptor class B type I) atherosclerosis.Moreover, vascular effects of HDL have been observed to be heterogenous and are altered in patients with CAD or diabetes, a condition that has been termed 'HDL dysfunction'.It will therefore be important to further determine, which biological functions of HDL are critical for its anti-atherosclerotic properties, as well as how these can be measured and targeted.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.

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Related in: MedlinePlus

Signalling pathways mediating the effects of HDL on endothelial NO productionHDL has been shown to stimulate endothelial NO synthase phosphorylation at serine residue 1177 via binding of apoA-I to SR-BI and binding of HDL-associated lysophospholipids to the S1P3 receptor. In addition, HDL-mediated efflux of 7-oxysterols via endothelial ABCG-1 has been observed to inhibit the interaction between eNOS and caveolin, and to prevent the loss of eNOS dimerization induced by reactive oxygen species in the endothelium.
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fig03: Signalling pathways mediating the effects of HDL on endothelial NO productionHDL has been shown to stimulate endothelial NO synthase phosphorylation at serine residue 1177 via binding of apoA-I to SR-BI and binding of HDL-associated lysophospholipids to the S1P3 receptor. In addition, HDL-mediated efflux of 7-oxysterols via endothelial ABCG-1 has been observed to inhibit the interaction between eNOS and caveolin, and to prevent the loss of eNOS dimerization induced by reactive oxygen species in the endothelium.

Mentions: Several different mechanisms have been proposed to account for the endothelial NO-stimulating capacity of HDL (Fig 3). Early studies have suggested that HDL acts by preventing the detrimental effects of oxidized LDL on endothelial NO-synthase (Uittenbogaard et al, 2000) while a subsequent study by Yuhanna et al (Yuhanna et al, 2001) suggested that HDL can bind to endothelial SR-BI and thus directly stimulate eNOS-mediated NO production. Mechanistically, binding of HDL to SR-BI initially leads to tyrosine kinase Src-mediated activation of phosphoinositide (PI) 3-kinase, which in turn activates Akt and the MAP kinase/extracellular signal-regulated kinase pathway (Mineo et al, 2003). This activation of endothelial Akt has been shown to stimulate phosphorylation of eNOS at serine residue 1177 (Mineo et al, 2003; Nofer et al, 2004), known to be an important regulatory mechanism leading to eNOS activation (Dimmeler et al, 1999). In contrast, the mechanism through which the MAP kinase/extracellular signal-regulated kinase pathway activates eNOS in endothelial cells stimulated with HDL remains to be further elucidated.


Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.

Besler C, Lüscher TF, Landmesser U - EMBO Mol Med (2012)

Signalling pathways mediating the effects of HDL on endothelial NO productionHDL has been shown to stimulate endothelial NO synthase phosphorylation at serine residue 1177 via binding of apoA-I to SR-BI and binding of HDL-associated lysophospholipids to the S1P3 receptor. In addition, HDL-mediated efflux of 7-oxysterols via endothelial ABCG-1 has been observed to inhibit the interaction between eNOS and caveolin, and to prevent the loss of eNOS dimerization induced by reactive oxygen species in the endothelium.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376856&req=5

fig03: Signalling pathways mediating the effects of HDL on endothelial NO productionHDL has been shown to stimulate endothelial NO synthase phosphorylation at serine residue 1177 via binding of apoA-I to SR-BI and binding of HDL-associated lysophospholipids to the S1P3 receptor. In addition, HDL-mediated efflux of 7-oxysterols via endothelial ABCG-1 has been observed to inhibit the interaction between eNOS and caveolin, and to prevent the loss of eNOS dimerization induced by reactive oxygen species in the endothelium.
Mentions: Several different mechanisms have been proposed to account for the endothelial NO-stimulating capacity of HDL (Fig 3). Early studies have suggested that HDL acts by preventing the detrimental effects of oxidized LDL on endothelial NO-synthase (Uittenbogaard et al, 2000) while a subsequent study by Yuhanna et al (Yuhanna et al, 2001) suggested that HDL can bind to endothelial SR-BI and thus directly stimulate eNOS-mediated NO production. Mechanistically, binding of HDL to SR-BI initially leads to tyrosine kinase Src-mediated activation of phosphoinositide (PI) 3-kinase, which in turn activates Akt and the MAP kinase/extracellular signal-regulated kinase pathway (Mineo et al, 2003). This activation of endothelial Akt has been shown to stimulate phosphorylation of eNOS at serine residue 1177 (Mineo et al, 2003; Nofer et al, 2004), known to be an important regulatory mechanism leading to eNOS activation (Dimmeler et al, 1999). In contrast, the mechanism through which the MAP kinase/extracellular signal-regulated kinase pathway activates eNOS in endothelial cells stimulated with HDL remains to be further elucidated.

Bottom Line: Studies in gene-targeted mice, however, have also indicated that increasing HDL-cholesterol plasma levels can either limit (e.g. apolipoprotein A-I) or accelerate (e.g. Scavenger receptor class B type I) atherosclerosis.Moreover, vascular effects of HDL have been observed to be heterogenous and are altered in patients with CAD or diabetes, a condition that has been termed 'HDL dysfunction'.It will therefore be important to further determine, which biological functions of HDL are critical for its anti-atherosclerotic properties, as well as how these can be measured and targeted.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.

Show MeSH
Related in: MedlinePlus