PMID- 21357511
OWN - NLM
STAT- MEDLINE
DCOM- 20110707
LR  - 20211203
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 300
IP  - 5
DP  - 2011 May
TI  - Rapamycin inhibits hydrogen peroxide-induced loss of vascular contractility.
PG  - H1583-94
LID - 10.1152/ajpheart.01084.2010 [doi]
AB  - Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has 
      been shown to extend the life span of mice, and oxidative stress plays critical 
      roles in vascular aging involving loss of compliance of arteries. We examined, 
      therefore, whether rapamycin has protective effects on the inhibition of vascular 
      contractility by hydrogen peroxide (H(2)O(2)). Prolonged (3 h) exposure to H(2)O(2) 
      induced complete loss of contraction of mouse aortic rings and mesenteric 
      (resistance) arteries to either KCl or phenylephrine, which was attenuated by 
      pretreatment with rapamycin. H(2)O(2)-induced loss of contractility was unaffected by 
      treatment with actinomycin D or cycloheximide, inhibitors of gene transcription 
      and protein synthesis, respectively. Western blot analysis showed that there was 
      no increase in phosphorylation of S6 kinase 1 (S6K) or factor 4E binding protein 
      1 (4EBP1) in response to H(2)O(2) treatment, suggesting involvement of the mTOR 
      complex-2 (mTORC2) rather than mTORC1. H(2)O(2) treatment inhibited phosphorylation 
      of the 20-kDa regulatory light chains of myosin (LC(2)(0)), which was partially 
      blocked by rapamycin treatment. Interestingly, the calcineurin inhibitors 
      cyclosporine A and FK506 were found to mimic the rapamycin effect, and rapamycin 
      inhibited calcineurin activation induced by H(2)O(2). We conclude that rapamycin 
      inhibits H(2)O(2)-induced loss of vascular contractility, likely through an 
      mTORC2-calcineurin pathway.
FAU - Gao, Ge
AU  - Gao G
AD  - Department of Biochemistry and Molecular Biology, Faculty of Medicine, Univ. of 
      Calgary, Calgary, Alberta, Canada.
FAU - Li, Jing-Jing
AU  - Li JJ
FAU - Li, Yuenan
AU  - Li Y
FAU - Li, Dong
AU  - Li D
FAU - Wang, Yuebing
AU  - Wang Y
FAU - Wang, Lifeng
AU  - Wang L
FAU - Tang, Xiang D
AU  - Tang XD
FAU - Walsh, Michael P
AU  - Walsh MP
FAU - Gui, Yu
AU  - Gui Y
FAU - Zheng, Xi-Long
AU  - Zheng XL
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110225
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Calcineurin Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Oxidants)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Aging/drug effects/physiology
MH  - Animals
MH  - Aorta/*drug effects/physiology
MH  - Calcineurin Inhibitors
MH  - Cyclosporine/pharmacology
MH  - Hydrogen Peroxide/*pharmacology
MH  - Immunosuppressive Agents/*pharmacology
MH  - Male
MH  - Mesenteric Arteries/*drug effects/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Animal
MH  - Oxidants/*pharmacology
MH  - Oxidative Stress/drug effects/physiology
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Tacrolimus/pharmacology
MH  - Vasoconstriction/*drug effects/physiology
EDAT- 2011/03/02 06:00
MHDA- 2011/07/08 06:00
CRDT- 2011/03/02 06:00
PHST- 2011/03/02 06:00 [entrez]
PHST- 2011/03/02 06:00 [pubmed]
PHST- 2011/07/08 06:00 [medline]
AID - ajpheart.01084.2010 [pii]
AID - 10.1152/ajpheart.01084.2010 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1583-94. doi: 
      10.1152/ajpheart.01084.2010. Epub 2011 Feb 25.