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Cardiovascular & Hematological Disorders-Drug Targets


ISSN (Print): 1871-529X
ISSN (Online): 2212-4063

Review Article

Role of AMPK in Diabetic Cardiovascular Complications: An Overview

Author(s): Karthika Nellaiappan, Veera Ganesh Yerra and Ashutosh Kumar*

Volume 19, Issue 1, 2019

Page: [5 - 13] Pages: 9

DOI: 10.2174/1871529X18666180508104929

Price: $65


Macrovascular complications of diabetes like cardiovascular diseases appear to be one of the leading causes of mortality. Current therapies aimed at counteracting the adverse effects of diabetes on cardiovascular system are found to be inadequate. Hence, there is a growing need in search of novel targets. Adenosine Monophosphate Activated Protein Kinase (AMPK) is one such promising target, as a plethora of evidences pointing to its cardioprotective role in pathological milieu like cardiac hypertrophy, atherosclerosis and heart failure. AMPK is a serine-threonine kinase, which gets activated in response to a cellular depriving energy status. It orchestrates cellular metabolic response to energy demand and is, therefore, often referred to as “metabolic master switch” of the cell. In this review, we provide an overview of patho-mechanisms of diabetic cardiovascular disease; highlighting the role of AMPK in the regulation of this condition, followed by a description of extrinsic modulators of AMPK as potential therapeutic tools.

Keywords: AMPK, diabetes, diabetic complications, cardiomyopathy, cardiovascular disease, atherosclerosis.

Graphical Abstract
Yerra, V.G.; Negi, G.; Sharma, S.S.; Kumar, A. Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy. Redox Biol., 2013, 1(1), 394-397.
Organization, W.H. Global report on diabetes; World Health Organization, 2016.
Kannel, W.B.; McGee, D.L. Diabetes and cardiovascular risk factors: the Framingham study. Circulation, 1979, 59(1), 8-13.
Ludwig, D.S. The glycemic index: Physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. JAMA, 2002, 287(18), 2414-2423.
Colhoun, H.M.; Betteridge, D.J.; Durrington, P.N.; Hitman, G.A.; Neil, H.A.W.; Livingstone, S.J.; Thomason, M.J.; Mackness, M.I.; Charlton-Menys, V.; Fuller, J.H. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial. Lancet, 2004, 364(9435), 685-696.
Lindholm, L.H.; Ibsen, H.; Dahlöf, B.; Devereux, R.B.; Beevers, G.; de Faire, U.; Fyhrquist, F.; Julius, S.; Kjeldsen, S.E.; Kristiansson, K. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet, 2002, 359(9311), 1004-1010.
Group, A.C. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med., 2008, 2008(358), 2560-2572.
Yerra, V.G.; Kumar, A. Adenosine monophosphate-activated protein kinase abates hyperglycaemia-induced neuronal injury in experimental models of diabetic neuropathy: effects on mitochondrial biogenesis, autophagy and neuroinflammation. Mol. Neurobiol., 2017, 54(3), 2301-2312.
Hardie, D.G.; Ross, F.A.; Hawley, S.A. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol., 2012, 13(4), 251.
Alonso, N.; Moliner, P.; Mauricio, D. Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv. Exp. Med. Biol., 2018, 1067, 197-217.
Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature, 2001, 414(6865), 813-820.
Sandireddy, R.; Yerra, V.G.; Areti, A.; Komirishetty, P.; Kumar, A. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int. J. Endocrinol., 2014, 2014, 674987.
Negi, G.; Kumar, A.; Joshi, R.P.; Ruby, P.; Sharma, S.S. Oxidative stress and diabetic neuropathy: current status of antioxidants. Institute of Integrative Omics and Applied Biotechnology Journal, 2011, 2(6), 71-78.
Bidasee, K.R.; Nallani, K.; Yu, Y.; Cocklin, R.R.; Zhang, Y.; Wang, M.; Dincer, Ü.D.; Besch, H.R. Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/ calcium-release channels. Diabetes, 2003, 52(7), 1825-1836.
Cooper, M.E. Importance of advanced glycation end products in diabetes-associated cardiovascular and renal disease. Am. J. Hypertens., 2004, 17(S3), 31S-38S.
Neely, J.; Rovetto, M.A.; Oram, J. Myocardial utilization of carbohydrate and lipids. Prog. Cardiovasc. Dis., 1972, 15(3), 289-329.
Jia, G.; DeMarco, V.G.; Sowers, J.R. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat. Rev. Endocrinol., 2016, 12(3), 144.
du Toit, E.; Donner, D.G. Myocardial insulin resistance: An overview of its causes, effects, and potential therapy.Insulin Resistance; InTech, 2012.
Galadari, S.; Rahman, A.; Pallichankandy, S.; Galadari, A.; Thayyullathil, F. Role of ceramide in diabetes mellitus: Evidence and mechanisms. Lipids Health Dis., 2013, 12(1), 98.
Chong, Z.Z.; Maiese, K. Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc. Diabetol., 2012, 11(1), 45.
Wilson, A.J.; Gill, E.K.; Abudalo, R.A.; Edgar, K.S.; Watson, C.J.; Grieve, D.J. Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting.Heart, 2017, heartjnl-2017-311448,
Lebeche, D.; Davidoff, A.J.; Hajjar, R.J. Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy. Nat. Rev. Cardiol., 2008, 5(11), 715.
Oliveira, S.M.J.; Ehtisham, J.; Redwood, C.S.; Ostman-Smith, I.; Blair, E.M.; Watkins, H. Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. J. Mol. Cell. Cardiol., 2003, 35(10), 1251-1255.
Kewalramani, G.; Rodrigues, B. AMP-activated protein kinase in the heart: role in cardiac glucose and fatty acid metabolism. Clin. Lipidol., 2009, 4(5), 643-661.
Coort, S.L.; Bonen, A.; van der Vusse, G.J.; Glatz, J.F.; Luiken, J.J. Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters. Mol. Cell. Biochem., 2007, 299(1-2), 5-18.
Chan, A.Y.; Soltys, C-L.M.; Young, M.E.; Proud, C.G.; Dyck, J.R. Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J. Biol. Chem., 2004, 279(31), 32771-32779.
Yerra, V.G.; Kalvala, A.K.; Kumar, A. Isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by SIRT1 activation in experimental diabetic neuropathy. J. Nutr. Biochem., 2017, 47, 41-52.
Kim, J.; Kundu, M.; Viollet, B.; Guan, K-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol., 2011, 13(2), 132.
Gonzalez, C.D.; Lee, M-S.; Marchetti, P.; Pietropaolo, M.; Towns, R.; Vaccaro, M.I.; Watada, H.; Wiley, J.W. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy, 2011, 7(1), 2-11.
Li, Y.; Xu, S.; Mihaylova, M.M.; Zheng, B.; Hou, X.; Jiang, B.; Park, O.; Luo, Z.; Lefai, E.; Shyy, J.Y-J. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab., 2011, 13(4), 376-388.
Herzig, S.; Shaw, R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol., 2018, 19(2), 121-135.
Mihaylova, M.M.; Shaw, R.J. The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism. Nat. Cell Biol., 2011, 13(9), 1016.
Montgomery, M.K.; Turner, N. Mitochondrial dysfunction and insulin resistance: an update. Endocr. Connect., 2015, 4(1), R1-R15.
Ewart, M-A.; Kennedy, S. AMPK and vasculoprotection. Pharmacol. Ther., 2011, 131(2), 242-253.
Dong, Y.; Zhang, M.; Liang, B.; Xie, Z.; Zhao, Z.; Asfa, S.; Choi, H.C.; Zou, M-H. Reduction of AMP-activated protein kinase α2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation, 2010, 121(6), 792-803.
Goodman, M.; Liu, Z.; Zhu, P.; Li, J. AMPK Activators as a drug for diabetes, cancer and cardiovascular disease. Pharm. Regul. Affairs: open access., 2014, 3(2), pii 118.
Cheng, Z.; Pang, T.; Gu, M.; Gao, A-H.; Xie, C-M.; Li, J-Y.; Nan, F-J.; Li, J. Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK. Biochimica et Biophysica Acta (BBA)-. General Subjects, 2006, 1760(11), 1682-1689.
Chen, K.; Li, G.; Geng, F.; Zhang, Z.; Li, J.; Yang, M.; Dong, L.; Gao, F. Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K–Akt signaling in diabetic rats. Apoptosis, 2014, 19(6), 946-957.
Wang, Y.; Huang, Y.; Lam, K.S.; Li, Y.; Wong, W.T.; Ye, H.; Lau, C-W.; Vanhoutte, P.M.; Xu, A. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc. Res., 2009, 82(3), 484-492.
Wang, Q.; Zhang, M.; Liang, B.; Shirwany, N.; Zhu, Y.; Zou, M-H. Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: The role of uncoupling protein 2. PLoS One, 2011, 6(9), e25436.
Kumar, A.; Negi, G.; Sharma, S. Neuroprotection by resveratrol in diabetic neuropathy: Concepts & mechanisms. Curr. Med. Chem., 2013, 20(36), 4640-4645.
Gledhill, J.R.; Montgomery, M.G.; Leslie, A.G.; Walker, J.E. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl. Acad. Sci. USA, 2007, 104(34), 13632-13637.
Chan, A.Y.; Dolinsky, V.W.; Soltys, C-L.M.; Viollet, B.; Baksh, S.; Light, P.E.; Dyck, J.R. Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt. J. Biol. Chem., 2008, 283(35), 24194-24201.
Um, J-H.; Park, S-J.; Kang, H.; Yang, S.; Foretz, M.; McBurney, M.W.; Kim, M.K.; Viollet, B.; Chung, J.H. AMP-activated protein kinase–deficient mice are resistant to the metabolic effects of resveratrol. Diabetes, 2010, 59(3), 554-563.
Meng, Z.; Jing, H.; Gan, L.; Li, H.; Luo, B. Resveratrol attenuated estrogen-deficient-induced cardiac dysfunction: Role of AMPK, SIRT1, and mitochondrial function. Am. J. Transl. Res., 2016, 8(6), 2641.
Cheng, P.W.; Ho, W.Y.; Su, Y.T.; Lu, P.J.; Chen, B.Z.; Cheng, W.H.; Lu, W.H.; Sun, G.C.; Yeh, T.C.; Hsiao, M. Resveratrol decreases fructose-induced oxidative stress, mediated by NADPH oxidase via an AMPK-dependent mechanism. Br. J. Pharmacol., 2014, 171(11), 2739-2750.
Corton, J.M.; Gillespie, J.G.; Hawley, S.A.; Hardie, D.G. 5-Aminoimidazole-4-Carboxamide Ribonucleoside. FEBS J., 1995, 229(2), 558-565.
Chen, B-l.; Ma, Y-d.; Meng, R-S.; Xiong, Z-j.; Wang, H-n.; Zeng, J-y.; Liu, C.; Dong, Y-g. Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro. Acta Pharmacol. Sin., 2010, 31(7), 798.
Bradley, E.A.; Eringa, E.C.; Stehouwer, C.D.; Korstjens, I.; van Nieuw Amerongen, G.P.; Musters, R.; Sipkema, P.; Clark, M.G.; Rattigan, S. Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion. Arterioscler. Thromb. Vasc. Biol., 2010, 30(6), 1137-1142.
Kristiansen, S.B.; Solskov, L.; Jessen, N.; Løfgren, B.; Schmitz, O.; Nielsen-Kudsk, J.E.; Nielsen, T.T.; Bøtker, H.E.; Lund, S. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases myocardial glucose uptake during reperfusion and induces late pre-conditioning: potential role of AMP-activated protein kinase. Basic Clin. Pharmacol. Toxicol., 2009, 105(1), 10-16.
Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J., 2000, 348(3), 607-614.
Group, U.P.D.S. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998, 352(9131), 854-865.
Calvert, J.W.; Gundewar, S.; Jha, S.; Greer, J.J.; Bestermann, W.H.; Tian, R.; Lefer, D.J. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS–mediated signaling. Diabetes, 2008, 57(3), 696-705.
Fu, Y-n.; Xiao, H.; Ma, X-w.; Jiang, S-y.; Xu, M.; Zhang, Y-y. Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation. Acta Pharmacol. Sin., 2011, 32(7), 879.
Xie, Z.; Lau, K.; Eby, B.; Lozano, P.; He, C.; Pennington, B.; Li, H.; Rathi, S.; Dong, Y.; Tian, R. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes, 2011, 60(6), 1770-1778.
Wang, X.; Yang, L.; Kang, L.; Li, J.; Yang, L.; Zhang, J.; Liu, J.; Zhu, M.; Zhang, Q.; Shen, Y. Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes. PLoS One, 2017, 12(8), e0182777.
Brunmair, B.; Staniek, K.; Gras, F.; Scharf, N.; Althaym, A.; Clara, R.; Roden, M.; Gnaiger, E.; Nohl, H.; Waldhäusl, W. Thiazolidinediones, like metformin, inhibit respiratory complex I. Diabetes, 2004, 53(4), 1052-1059.
Hu, Y.; Liu, H.B.; Simpson, R.W.; Dear, A.E. PPARγ-independent thiazolidinedione-mediated inhibition of NUR77 expression in vascular endothelial cells. J. Endocrinol., 2011, 208(1), R1-R7.
Boyle, J.G.; Logan, P.J.; Ewart, M-A.; Reihill, J.A.; Ritchie, S.A.; Connell, J.M.; Cleland, S.J.; Salt, I.P. Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase. J. Biol. Chem., 2008, 283(17), 11210-11217.
Ceolotto, G.; Gallo, A.; Papparella, I.; Franco, L.; Murphy, E.; Iori, E.; Pagnin, E.; Fadini, G.P.; Albiero, M.; Semplicini, A. Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD (P) H oxidase via AMPK-dependent mechanism. Arterioscler. Thromb. Vasc. Biol., 2007, 27(12), 2627-2633.
Göransson, O.; McBride, A.; Hawley, S.A.; Ross, F.A.; Shpiro, N.; Foretz, M.; Viollet, B.; Hardie, D.G.; Sakamoto, K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem., 2007, 282(45), 32549-32560.
Kim, A.S.; Miller, E.J.; Wright, T.M.; Li, J.; Qi, D.; Atsina, K.; Zaha, V.; Sakamoto, K.; Young, L.H. A small molecule AMPK activator protects the heart against ischemia–reperfusion injury. J. Mol. Cell. Cardiol., 2011, 51(1), 24-32.
Timmermans, A.D.; Balteau, M.; Gélinas, R.; Renguet, E.; Ginion, A.; de Meester, C.; Sakamoto, K.; Balligand, J-L.; Bontemps, F.; Vanoverschelde, J-L. A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake. Am. J. Physiol. Heart Circ. Physiol., 2014, 306(12), H1619-H1630.

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