PMID- 22028412
OWN - NLM
STAT- MEDLINE
DCOM- 20120216
LR  - 20211203
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 302
IP  - 2
DP  - 2012 Jan 15
TI  - Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial 
      nitric oxide synthase and vasodilation.
PG  - E201-8
LID - 10.1152/ajpendo.00497.2011 [doi]
AB  - Elevated tissue levels of angiotensin II (ANG II) are associated with impairment 
      of insulin actions in metabolic and cardiovascular tissues. ANG II-stimulated 
      activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in 
      cardiovascular tissues is implicated in cardiac hypertrophy and vascular 
      remodeling. However, the role of ANG II-stimulated mTOR/p70S6K in vascular 
      endothelium is poorly understood. In the present study, we observed that ANG II 
      stimulated p70S6K in bovine aortic endothelial cells. ANG II increased 
      phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser(636/639) and 
      inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide 
      synthase (eNOS). An inhibitor of mTOR, rapamycin, attenuated the ANG 
      II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 
      (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated 
      phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole 
      vasodilation. Moreover, point mutations of IRS-1 at Ser(636/639) to Ala prevented 
      the ANG II-mediated inhibition of insulin signaling. From these results, we 
      conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may 
      contribute to impairment of insulin-stimulated vasodilation through 
      phosphorylation of IRS-1 at Ser(636/639). This ANG II-mediated impairment of 
      vascular actions of insulin may help explain the role of ANG II as a link between 
      insulin resistance and hypertension.
FAU - Kim, Jeong-A
AU  - Kim JA
AD  - Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, 
      Universityof Alabama at Birmingham Comprehensive Diabetes Center, AL 35294, USA. 
      jakim@uab.edu
FAU - Jang, Hyun-Ju
AU  - Jang HJ
FAU - Martinez-Lemus, Luis A
AU  - Martinez-Lemus LA
FAU - Sowers, James R
AU  - Sowers JR
LA  - eng
GR  - R01 HL073101/HL/NHLBI NIH HHS/United States
GR  - R01-HL-73101-01A1/HL/NHLBI NIH HHS/United States
GR  - R01 HL088105/HL/NHLBI NIH HHS/United States
GR  - R01-HL-088105-01A1/HL/NHLBI NIH HHS/United States
GR  - P60 DK-079626/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20111025
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 11128-99-7 (Angiotensin II)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Angiotensin II/*pharmacology
MH  - Animals
MH  - Cattle
MH  - Cells, Cultured
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Endothelium, Vascular/cytology/drug effects/*metabolism
MH  - Insulin/*pharmacology
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Male
MH  - Nitric Oxide Synthase Type III/*metabolism
MH  - Phosphorylation/drug effects/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Vasodilation/drug effects/*physiology
PMC - PMC3340897
EDAT- 2011/10/27 06:00
MHDA- 2012/02/18 06:00
PMCR- 2013/01/15
CRDT- 2011/10/27 06:00
PHST- 2011/10/27 06:00 [entrez]
PHST- 2011/10/27 06:00 [pubmed]
PHST- 2012/02/18 06:00 [medline]
PHST- 2013/01/15 00:00 [pmc-release]
AID - ajpendo.00497.2011 [pii]
AID - E-00497-2011 [pii]
AID - 10.1152/ajpendo.00497.2011 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2012 Jan 15;302(2):E201-8. doi: 
      10.1152/ajpendo.00497.2011. Epub 2011 Oct 25.