PMID- 12511559
OWN - NLM
STAT- MEDLINE
DCOM- 20030514
LR  - 20220310
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 11
DP  - 2003 Mar 14
TI  - High density lipoprotein-induced endothelial nitric-oxide synthase activation is 
      mediated by Akt and MAP kinases.
PG  - 9142-9
AB  - 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 (10-50 microg/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.
FAU - Mineo, Chieko
AU  - Mineo C
AD  - Department of Pediatrics, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA. chieko.mineo@utsouthwestern.edu
FAU - Yuhanna, Ivan S
AU  - Yuhanna IS
FAU - Quon, Michael J
AU  - Quon MJ
FAU - Shaul, Philip W
AU  - Shaul PW
LA  - eng
GR  - HL 30276/HL/NHLBI NIH HHS/United States
GR  - HL 53546/HL/NHLBI NIH HHS/United States
GR  - HL 58888/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030102
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Complementary)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipoproteins, HDL)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 452VLY9402 (Serine)
RN  - EC 1.14.13.39 (NOS3 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - COS Cells
MH  - Cattle
MH  - Cells, Cultured
MH  - DNA, Complementary/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Endothelium/cytology
MH  - Endothelium, Vascular/cytology
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Genes, Dominant
MH  - Humans
MH  - Lipoproteins, HDL/*metabolism
MH  - *MAP Kinase Signaling System
MH  - Models, Biological
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase/*metabolism
MH  - Nitric Oxide Synthase Type III
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - *Protein Serine-Threonine Kinases
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Serine/metabolism
MH  - Sheep
MH  - Signal Transduction
MH  - Time Factors
MH  - Transfection
EDAT- 2003/01/04 04:00
MHDA- 2003/05/15 05:00
CRDT- 2003/01/04 04:00
PHST- 2003/01/04 04:00 [pubmed]
PHST- 2003/05/15 05:00 [medline]
PHST- 2003/01/04 04:00 [entrez]
AID - S0021-9258(19)71284-8 [pii]
AID - 10.1074/jbc.M211394200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Mar 14;278(11):9142-9. doi: 10.1074/jbc.M211394200. Epub 2003 
      Jan 2.