Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling

• DOI: 10.1161/hh2401.101385
• Publication Date: 2007-09-28T18:32:49Z
• Authors: Anne K. Jonassen; Michael N. Sack; Ole D. Mjøs; Derek M. Yellon
• Keywords: Cardioprotection; Wortmannin

The “metabolic cocktail” comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the vivo rat heart. We propose that insulin is major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied isolated perfused hearts (measuring to area of risk [%]) subjected 35 minutes regional myocardial ischemia 2 hours reperfusion. Insulin administered onset attenuated by ≥45% versus control ( P <0.001). Insulin-mediated cardioprotection found be independent presence glucose Moreover, cell survival benefit temporally dependent, administration from maintained for either 15 or duration reduced size. In contrast, abrogated if delayed until into Pharmacological inhibition both upstream downstream signals pathway abolished cardioprotective effects insulin. Here coadministration with tyrosine kinase inhibitor lavendustin A, phosphatidylinositol3-kinase (PI3-kinase) wortmannin, mTOR/p70s6 rapamycin cardioprotection. Steady-state levels activated/phosphorylated correlated administration. Finally, targets including p70s6 BAD were modulated conclusion, infarction, dependent on early during reperfusion, mediated signaling pathway. its inert phosphorylated state response therapy.