PMID- 10376603
OWN - NLM
STAT- MEDLINE
DCOM- 19990630
LR  - 20191210
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 399
IP  - 6736
DP  - 1999 Jun 10
TI  - Activation of nitric oxide synthase in endothelial cells by Akt-dependent
      phosphorylation.
PG  - 601-5
AB  - Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is a fundamental
      determinant of cardiovascular homesotasis: it regulates systemic blood pressure, 
      vascular remodelling and angiogenesis. Physiologically, the most important
      stimulus for the continuous formation of NO is the viscous drag (shear stress)
      generated by the streaming blood on the endothelial layer. Although
      shear-stress-mediated phosphorylation of eNOS is thought to regulate enzyme
      activity, the mechanism of activation of eNOS is not yet known. Here we
      demonstrate that the serine/threonine protein kinase Akt/PKB mediates the
      activation of eNOS, leading to increased NO production. Inhibition of the
      phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS 
      protein (at serine 1177) attenuates the serine phosphorylation and prevents the
      activation of eNOS. Mimicking the phosphorylation of Ser 1177 directly enhances
      enzyme activity and alters the sensitivity of the enzyme to Ca2+, rendering its
      activity maximal at sub-physiological concentrations of Ca2+. Thus,
      phosphorylation of eNOS by Akt represents a novel Ca2+-independent regulatory
      mechanism for activation of eNOS.
FAU - Dimmeler, S
AU  - Dimmeler S
AD  - Molecular Cardiology, Department of Internal Medicine IV, University of
      Frankfurt, Germany.
FAU - Fleming, I
AU  - Fleming I
FAU - Fisslthaler, B
AU  - Fisslthaler B
FAU - Hermann, C
AU  - Hermann C
FAU - Busse, R
AU  - Busse R
FAU - Zeiher, A M
AU  - Zeiher AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Androstadienes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
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 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Cell Line
MH  - Endothelium, Vascular/*enzymology
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase/genetics/*metabolism
MH  - Nitric Oxide Synthase Type III
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - *Protein-Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Serine/metabolism
MH  - Swine
MH  - Wortmannin
EDAT- 1999/06/22 10:00
MHDA- 2001/03/23 10:01
CRDT- 1999/06/22 10:00
PHST- 1999/06/22 10:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/06/22 10:00 [entrez]
AID - 10.1038/21224 [doi]
PST - ppublish
SO  - Nature. 1999 Jun 10;399(6736):601-5. doi: 10.1038/21224.