High Density Lipoprotein-induced Endothelial Nitric-oxide Synthase Activation Is Mediated by Akt and MAP Kinases
High density lipoprotein (HDL) activates endothelial nitric-oxide synthase (eNOS), leading to increased production of the antiatherogenic molecule NO. A variety of stimuli regulate eNOS activity through signaling pathways involving Akt kinase and/or mitogen-activated protein (MAP) kinase. In the pre...
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Published in | The Journal of biological chemistry Vol. 278; no. 11; pp. 9142 - 9149 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
14.03.2003
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Subjects | |
Online Access | Get full text |
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Summary: | High density lipoprotein (HDL) activates endothelial nitric-oxide synthase (eNOS), leading to increased production of the
antiatherogenic molecule NO. A variety of stimuli regulate eNOS activity through signaling pathways involving Akt kinase and/or
mitogen-activated protein (MAP) kinase. In the present study, we investigated the role of kinase cascades in HDL-induced eNOS
stimulation in cultured endothelial cells and COS M6 cells transfected with eNOS and the HDL receptor, scavenger receptor
B-I. HDL (10â50 μg/ml, 20 min) caused eNOS phosphorylation at Ser-1179, and dominant negative Akt inhibited both HDL-mediated
phosphorylation and activation of the enzyme. Phosphoinositide 3-kinase (PI3 kinase) inhibition or dominant negative PI3 kinase
also blocked the phosphorylation and activation of eNOS by HDL. Studies with genistein and PP2 showed that the nonreceptor
tyrosine kinase, Src, is an upstream stimulator of the PI3 kinase-Akt pathway in this paradigm. In addition, HDL activated
MAP kinase through PI3 kinase, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibition
fully attenuated eNOS stimulation by HDL without affecting Akt or eNOS Ser-1179 phosphorylation. Conversely, dominant negative
Akt did not alter HDL-induced MAP kinase activation. These results indicate that HDL stimulates eNOS through common upstream,
Src-mediated signaling, which leads to parallel activation of Akt and MAP kinases and their resultant independent modulation
of the enzyme. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M211394200 |