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Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation.
Crit Care Med. 2008 May; 36(5):1551-8.CC

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.

Authors+Show Affiliations

Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18434880

Citation

Li, Jia, et al. "Insulin Inhibits Tumor Necrosis Factor-alpha Induction in Myocardial Ischemia/reperfusion: Role of Akt and Endothelial Nitric Oxide Synthase Phosphorylation." Critical Care Medicine, vol. 36, no. 5, 2008, pp. 1551-8.
Li J, Zhang H, Wu F, et al. Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Crit Care Med. 2008;36(5):1551-8.
Li, J., Zhang, H., Wu, F., Nan, Y., Ma, H., Guo, W., Wang, H., Ren, J., Das, U. N., & Gao, F. (2008). Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Critical Care Medicine, 36(5), 1551-8. https://doi.org/10.1097/CCM.0b013e3181782335
Li J, et al. Insulin Inhibits Tumor Necrosis Factor-alpha Induction in Myocardial Ischemia/reperfusion: Role of Akt and Endothelial Nitric Oxide Synthase Phosphorylation. Crit Care Med. 2008;36(5):1551-8. PubMed PMID: 18434880.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. AU - Li,Jia, AU - Zhang,Haifeng, AU - Wu,Feng, AU - Nan,Ying, AU - Ma,Heng, AU - Guo,Wenyi, AU - Wang,Haichang, AU - Ren,Jun, AU - Das,Undurti N, AU - Gao,Feng, PY - 2008/4/25/pubmed PY - 2008/6/5/medline PY - 2008/4/25/entrez SP - 1551 EP - 8 JF - Critical care medicine JO - Crit Care Med VL - 36 IS - 5 N2 - 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. SN - 1530-0293 UR - https://www.unboundmedicine.com/medline/citation/18434880/Insulin_inhibits_tumor_necrosis_factor_alpha_induction_in_myocardial_ischemia/reperfusion:_role_of_Akt_and_endothelial_nitric_oxide_synthase_phosphorylation_ L2 - https://dx.doi.org/10.1097/CCM.0b013e3181782335 DB - PRIME DP - Unbound Medicine ER -