Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.
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.
Affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.Show MeSH
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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.
Affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.