Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation.
OBJECTIVE
Intensive insulin therapy with tight glucose control is known to result in reduced morbidity and mortality in inflammation-related critical illness. Tumor necrosis factor (TNF)-alpha induction in myocardial infarction may trigger inflammation and have detrimental effects on cardiomyocytes. This study was designed to investigate whether insulin attenuates TNF-alpha induction in acute myocardial ischemia/reperfusion (MI/R) and the underlying signaling mechanisms.


METHODS
Randomized experimental study.


METHODS
Research laboratory.


METHODS
Sprague-Dawley rats.


METHODS
Anesthetized rats were subjected to MI/R (30 mins/3 hrs) and were treated with saline, glucose-insulin-potassium, or glucose-potassium infusion (4 mL/kg/hr intravenously). In vitro study was performed on cultured cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R).


RESULTS
In vivo treatment with glucose-insulin-potassium, but not glucose-potassium, significantly attenuated inflammatory response as evidenced by decreased TNF-alpha induction and myocardial myeloperoxidase activity, with concurrent reduction in creatine kinase activity and myocardial infarction compared with those in control rats. In cultured cardiomyocytes subjected to SI/R, insulin reduced TNF-alpha induction and increased Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and subsequent nitric oxide (NO) production. Inhibition of insulin-stimulated NO production using either the PI3K inhibitor wortmannin or the NOS inhibitor L-NAME blocked TNF-alpha reduction afforded by insulin. Furthermore, the suppression on TNF-alpha by either insulin or TNF-alpha neutralizing antibody improved viability and reduced apoptosis of cardiomyocytes subjected to SI/R.


CONCLUSIONS
Our data showed that insulin inhibits ischemia/reperfusion-induced TNF-alpha production through the Akt-activated and eNOS-NO-dependent pathway in cardiomyocytes. The anti-inflammatory property elicited by insulin may contribute to its cardioprotective and prosurvival effects in the critically ill.
Li
Jia
J
Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Zhang
Haifeng
H
Wu
Feng
F
Nan
Ying
Y
Ma
Heng
H
Guo
Wenyi
W
Wang
Haichang
H
Ren
Jun
J
Das
Undurti N
UN
Gao
Feng
F
D000818:Animals; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*
D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt