AMPK-regulated and Akt-dependent Enhancement of Glucose Uptake is Essential in Ischemic Preconditioning-alleviated Reperfusion Injury

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Aug 8

PMID 23922853

Citations 34

Authors

Lele Ji

Xing Zhang

Wenchong Liu

Qichao Huang

Weidong Yang

Feng Fu

Heng Ma

Hui Su

Haichang Wang

Jing Wang

Haifeng Zhang

Feng Gao

Affiliations

Soon will be listed here.

Abstract

Aims: Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury.

Methods: Normal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by (18)F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay.

Results: IPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05).

Conclusions: The present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK and Akt in reperfused myocardium is essential to IPC-alleviated reperfusion injury. This intrinsic metabolic modulation and cardioprotective capacity are present in STZ-treated hearts and can be triggered by insulin.

Citing Articles

Mitochondrial Kinase Signaling for Cardioprotection.

Boengler K, Eickelmann C, Kleinbongard P Int J Mol Sci. 2024; 25(8).

PMID: 38674076 PMC: 11049936. DOI: 10.3390/ijms25084491.

Exercise preconditioning promotes myocardial GLUT4 translocation and induces autophagy to alleviate exhaustive exercise-induced myocardial injury in rats.

Guo Y, Pan S, Chen T, Huang Y, Wan D, Tong Y J Mol Histol. 2023; 54(5):453-472.

PMID: 37715078 DOI: 10.1007/s10735-023-10152-7.

Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of salidroside on intestine ischemia reperfusion.

Chen F, Chai Y, Zhang F, Liu Y, Zhang Y, Shi Y Biosci Rep. 2023; 43(8).

PMID: 37530723 PMC: 10462912. DOI: 10.1042/BSR20230539.

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning.

Ferdinandy P, Andreadou I, Baxter G, Botker H, Davidson S, Dobrev D Pharmacol Rev. 2023; 75(1):159-216.

PMID: 36753049 PMC: 9832381. DOI: 10.1124/pharmrev.121.000348.

An Overview of the Molecular Mechanisms Associated with Myocardial Ischemic Injury: State of the Art and Translational Perspectives.

Schirone L, Forte M, DAmbrosio L, Valenti V, Vecchio D, Schiavon S Cells. 2022; 11(7).

PMID: 35406729 PMC: 8998015. DOI: 10.3390/cells11071165.

References

Crozier S, Zhang X, Wang J, Cheung J, Kimball S, Jefferson L . Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion. J Appl Physiol (1985). 2006; 101(2):576-82. PMC: 2631174. DOI: 10.1152/japplphysiol.01122.2005. View

Murry C, Jennings R, Reimer K . Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74(5):1124-36. DOI: 10.1161/01.cir.74.5.1124. View

Tong H, Chen W, London R, Murphy E, Steenbergen C . Preconditioning enhanced glucose uptake is mediated by p38 MAP kinase not by phosphatidylinositol 3-kinase. J Biol Chem. 2000; 275(16):11981-6. DOI: 10.1074/jbc.275.16.11981. View

Katakam P, Jordan J, Snipes J, Tulbert C, Miller A, Busija D . Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol. 2006; 292(2):R920-6. DOI: 10.1152/ajpregu.00520.2006. View

Sukhodub A, Jovanovic S, Du Q, Budas G, Clelland A, Shen M . AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol. 2006; 210(1):224-36. PMC: 2128052. DOI: 10.1002/jcp.20862. View

Zhang Q, Li Q, Zhang H, Zhang K, Guo W, Wang H . Swim training sensitizes myocardial response to insulin: role of Akt-dependent eNOS activation. Cardiovasc Res. 2007; 75(2):369-80. DOI: 10.1016/j.cardiores.2007.04.015. View

Si R, Tao L, Zhang H, Yu Q, Zhang R, Lv A . Survivin: a novel player in insulin cardioprotection against myocardial ischemia/reperfusion injury. J Mol Cell Cardiol. 2010; 50(1):16-24. DOI: 10.1016/j.yjmcc.2010.08.017. View

Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K . Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction. J Am Coll Cardiol. 2001; 38(4):1007-11. DOI: 10.1016/s0735-1097(01)01477-2. View

Ashrafian H, Frenneaux M, Opie L . Metabolic mechanisms in heart failure. Circulation. 2007; 116(4):434-48. DOI: 10.1161/CIRCULATIONAHA.107.702795. View

10.

Vaughn A, Deshmukh M . Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol. 2008; 10(12):1477-83. PMC: 2626347. DOI: 10.1038/ncb1807. View

11.

Opie L, Sack M . Metabolic plasticity and the promotion of cardiac protection in ischemia and ischemic preconditioning. J Mol Cell Cardiol. 2002; 34(9):1077-89. DOI: 10.1006/jmcc.2002.2066. View

12.

Hu Z, Chen J, Wei Q, Xia Y . Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function: co-commitment and interplay of Akt and AMPK. J Biol Chem. 2008; 283(37):25256-25263. PMC: 2533089. DOI: 10.1074/jbc.M802455200. View

13.

Fischer-Rasokat U, Beyersdorf F, Doenst T . Insulin addition after ischemia improves recovery of function equal to ischemic preconditioning in rat heart. Basic Res Cardiol. 2003; 98(5):329-36. DOI: 10.1007/s00395-003-0414-y. View

14.

Gao F, Gao E, Yue T, Ohlstein E, Lopez B, Christopher T . Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation. 2002; 105(12):1497-502. DOI: 10.1161/01.cir.0000012529.00367.0f. View

15.

Tian R, Balschi J . Interaction of insulin and AMPK in the ischemic heart: another chapter in the book of metabolic therapy?. Circ Res. 2006; 99(1):3-5. DOI: 10.1161/01.RES.0000233142.26369.f6. View

16.

Ebel D, Mullenheim J, Frassdorf J, Heinen A, Huhn R, Bohlen T . Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo. Pflugers Arch. 2003; 446(2):175-82. DOI: 10.1007/s00424-003-1051-x. View

17.

Lopaschuk G . AMP-activated protein kinase control of energy metabolism in the ischemic heart. Int J Obes (Lond). 2008; 32 Suppl 4:S29-35. DOI: 10.1038/ijo.2008.120. View

18.

Towler M, Grahame Hardie D . AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007; 100(3):328-41. DOI: 10.1161/01.RES.0000256090.42690.05. View

19.

Li Q, Xiong Z, Hu B, Tian Z, Zhang H, Gou W . Aging-associated insulin resistance predisposes to hypertension and its reversal by exercise: the role of vascular vasorelaxation to insulin. Basic Res Cardiol. 2008; 104(3):269-84. DOI: 10.1007/s00395-008-0754-8. View

20.

Lee M, Ko J, Lee A, Lee I, Jung M, Austin B . Effects of anesthetic protocol on normal canine brain uptake of 18F-FDG assessed by PET/CT. Vet Radiol Ultrasound. 2010; 51(2):130-5. DOI: 10.1111/j.1740-8261.2009.01636.x. View