PMID- 11739285
OWN - NLM
STAT- MEDLINE
DCOM- 20020123
LR  - 20211203
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 89
IP  - 12
DP  - 2001 Dec 7
TI  - Myocardial protection by insulin at reperfusion requires early administration and 
      is mediated via Akt and p70s6 kinase cell-survival signaling.
PG  - 1191-8
AB  - The "metabolic cocktail" comprising glucose-insulin-potassium administrated at 
      reperfusion reduces infarct size in the in vivo rat heart. We propose that 
      insulin is the major component mediating this protection and acts via Akt 
      prosurvival signaling. This hypothesis was studied in isolated perfused rat 
      hearts (measuring infarct size to area of risk [%]) subjected to 35 minutes 
      regional myocardial ischemia and 2 hours reperfusion. Insulin administered at the 
      onset of reperfusion attenuated infarct size by >/=45% versus control hearts 
      (P<0.001). Insulin-mediated cardioprotection was found to be independent of the 
      presence of glucose at reperfusion. Moreover, the cell survival benefit of 
      insulin is temporally dependent, in that insulin administration from the onset of 
      reperfusion and maintained for either 15 minutes or for the duration of 
      reperfusion reduced infarct size. In contrast, protection was abrogated if 
      insulin administration was delayed until 15 minutes into reperfusion. 
      Pharmacological inhibition of both upstream and downstream signals in the Akt 
      prosurvival pathway abolished the cardioprotective effects of insulin. Here 
      coadministration of insulin with the tyrosine kinase inhibitor lavendustin A, the 
      phosphatidylinositol3-kinase (PI3-kinase) inhibitor wortmannin, and mTOR/p70s6 
      kinase inhibitor rapamycin abolished cardioprotection. Steady-state levels of 
      activated/phosphorylated Akt correlated with insulin administration. Finally, 
      downstream prosurvival targets of Akt including p70s6 kinase and BAD were 
      modulated by insulin. In conclusion, insulin administration at reperfusion 
      reduces myocardial infarction, is dependent on early administration during 
      reperfusion, and is mediated via Akt and p70s6 kinase dependent signaling 
      pathway. Moreover, BAD is maintained in its inert phosphorylated state in 
      response to insulin therapy.
FAU - Jonassen, A K
AU  - Jonassen AK
AD  - Department of Medical Physiology, Institute of Medical Biology, University of 
      Tromso, Norway.
FAU - Sack, M N
AU  - Sack MN
FAU - Mjos, O D
AU  - Mjos OD
FAU - Yellon, D M
AU  - Yellon DM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Bad protein, rat)
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (bcl-Associated Death Protein)
RN  - 8558G7RUTR (Pyruvic Acid)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/metabolism
MH  - Cell Survival/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Glucose/metabolism
MH  - Heart/*drug effects/physiology
MH  - In Vitro Techniques
MH  - Insulin/*pharmacology
MH  - Male
MH  - Myocardial Infarction/pathology/prevention & control
MH  - Myocardial Reperfusion
MH  - Myocardium/*metabolism/pathology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors
MH  - Protein Kinases/metabolism
MH  - *Protein Serine-Threonine Kinases
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Pyruvic Acid/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Ribosomal Protein S6 Kinases/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - bcl-Associated Death Protein
EDAT- 2001/12/12 10:00
MHDA- 2002/01/24 10:01
CRDT- 2001/12/12 10:00
PHST- 2001/12/12 10:00 [pubmed]
PHST- 2002/01/24 10:01 [medline]
PHST- 2001/12/12 10:00 [entrez]
AID - 10.1161/hh2401.101385 [doi]
PST - ppublish
SO  - Circ Res. 2001 Dec 7;89(12):1191-8. doi: 10.1161/hh2401.101385.