Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation.

Abstract:

OBJECTIVES: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. DESIGN:Randomized experimental study. SETTING:Research laboratory. SUBJECTS:Sprague-Dawley rats. INTERVENTIONS: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). MEASUREMENTS AND MAIN 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.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Li J,Zhang H,Wu F,Nan Y,Ma H,Guo W,Wang H,Ren J,Das UN,Gao F

doi

10.1097/CCM.0b013e3181782335

subject

Has Abstract

pub_date

2008-05-01 00:00:00

pages

1551-8

issue

5

eissn

0090-3493

issn

1530-0293

journal_volume

36

pub_type

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