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Cardiovascular Research 2006 69(1):57-65; doi:10.1016/j.cardiores.2005.08.019
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Copyright © 2005, European Society of Cardiology

Vasculoprotective effect of insulin in the ischemic/reperfused canine heart: Role of Akt-stimulated NO production

Heng Maa, Hai-Feng Zhanga, Lu Yua, Quan-Jiang Zhanga, Jia Lia, Jian-Hua Huoa, Xue Lib, Wen-Yi Guob, Hai-Chang Wangb and Feng Gaoa,b,*

aDepartment of Physiology, Fourth Military Medical University, Xi'an, 710032, China
bDepartment of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China

* Corresponding author. Department of Physiology and Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Tel.: +86 29 83376423; fax: +86 29 83376423. Email address: fgao{at}fmmu.edu.cn

Objectives: The objectives of this study were to investigate the vasculoprotective effects of glucose–insulin–potassium (GIK) on ischemia/reperfusion-induced coronary endothelial functional injury and to elucidate the mechanism involved.

Methods: Dogs were subjected to 50 min of coronary occlusion and 4 h of reperfusion. Vehicle, GIK, or GK were intravenously infused 5 min before reperfusion, and the coronary vascular dysfunction and endothelial apoptosis were determined. In a separate study, cultured endothelial cells were subjected to simulated ischemia/reperfusion, and the signaling pathway involved in insulin's anti-apoptotic effect was investigated.

Results: In vivo ischemia/reperfusion caused significant coronary vascular endothelial dysfunction as evidenced by reduced endothelium-dependent vasorelaxation, decreased nitric oxide (NO) production, and endothelial cell apoptosis as determined by caspase 3 activation and TUNEL staining. Treatment with GIK, but not GK, markedly improved the endothelium-dependent coronary vasorelaxation (P<0.01 versus vehicle), increased total NO production (P<0.01), and attenuated endothelial apoptosis. In cultured endothelial cells, treatment with insulin also markedly increased NO production and reduced simulated ischemia/reperfusion-induced apoptosis. Moreover, pre-treatment with either Akt inhibitor or NO synthase inhibitor almost abolished the anti-apoptotic effect exerted by insulin but not by SNAP, an NO donor.

Conclusion: These results demonstrate that in vivo treatment with GIK at reperfusion attenuates ischemia/reperfusion-induced coronary endothelial dysfunction and endothelial apoptosis in an Akt-dependent and NO-mediated fashion. The coronary vasculoprotective effect elicited by insulin may contribute to the previously observed cardiac protective effect of GIK.

KEYWORDS Insulin; Endothelial dysfunction; Reperfusion injury; Apoptosis; Nitric oxide

Time for primary review 24 days


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