Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases
Li Tian1, Mu Nan1, Yin Yue1, Yu Lu2,*, Ma Heng1,*
1Department of physiology and pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China 2Department of pathology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Aging is a pivotal risk factor for developing cardiovascular diseases (CVD) due to the lifelong exposure to various risk factors that may affect the heart and vasculature during aging. AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, is a pivotal endogenous energy regulator that protects against various pathological alterations. In this report, we first introduced the protective mechanisms of AMPK signaling in myocardium, such as oxidative stress, apoptosis, inflammation, autophagy and inflammatory response. Next, we introduced the potential correlation between AMPK and cardiac aging. Then, we highlighted the roles of AMPK signaling in cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Lastly, some potential directions and further perspectives were expanded. The information extends our understanding on the protective roles of AMPK in myocardial aging, which may contribute to the design of drug targets and sheds light on potential treatments of AMPK for aging-related CVD.
AMPK activation inhibits mRNA and protein levels of pro-inflammatory cytokines, such as TNF-α and IL-6
Chen et al. (2018) 
Table 1 Protective mechanisms of AMPK signaling in myocardium.
Alfaras I, Di Germanio C, Bernier M, Csiszar A, Ungvari Z, Lakatta EG, et al. (2016). Pharmacological Strategies to Retard Cardiovascular Aging. Circ Res, 118:1626-1642.
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. (2019). Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation, 139:e56-e528.
Bittner VA (2019). The New 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation.
Turdi S, Fan X, Li J, Zhao J, Huff AF, Du M, et al. (2010). AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell, 9:592-606.
McClellan M, Brown N, Califf RM, Warner JJ (2019). Call to Action: Urgent Challenges in Cardiovascular Disease: A Presidential Advisory From the American Heart Association. Circulation, 139:e44-e54.
Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD (1995). High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem, 270:17513-17520.
Sambandam N, Lopaschuk GD (2003). AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog Lipid Res, 42:238-256.
Salt IP, Hardie DG (2017). AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System. Circ Res, 120:1825-1841.
Lu Q, Li X, Liu J, Sun X, Rousselle T, Ren D, et al. (2019). AMPK is associated with the beneficial effects of antidiabetic agents on cardiovascular diseases. Biosci Rep, 39.
Feng Y, Lu Y, Liu D, Zhang W, Liu J, Tang H, et al. (2018). Apigenin-7-O-beta-d-(-6''-p-coumaroyl)-glucopyranoside pretreatment attenuates myocardial ischemia/reperfusion injury via activating AMPK signaling. Life Sci, 203:246-254.
Slamova K, Papousek F, Janovska P, Kopecky J, Kolar F (2016). Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high-fat diet on heart function and ischemic tolerance in aged female mice. Physiol Res, 65:33-42.
van der Pol A, van Gilst WH, Voors AA, van der Meer P (2019). Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail, 21:425-435.
Munzel T, Camici GG, Maack C, Bonetti NR, Fuster V, Kovacic JC (2017). Impact of Oxidative Stress on the Heart and Vasculature: Part 2 of a 3-Part Series. J Am Coll Cardiol, 70:212-229.
Li X, Wu D, Tian Y (2018). Fibroblast growth factor 19 protects the heart from oxidative stress-induced diabetic cardiomyopathy via activation of AMPK/Nrf2/HO-1 pathway. Biochem Biophys Res Commun, 502:62-68.
Yang H, Feng A, Lin S, Yu L, Lin X, Yan X, et al. (2018). Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis, 9:227.
Zhao C, Zhang Y, Liu H, Li P, Zhang H, Cheng G (2017). Fortunellin protects against high fructose-induced diabetic heart injury in mice by suppressing inflammation and oxidative stress via AMPK/Nrf-2 pathway regulation. Biochem Biophys Res Commun, 490:552-559.
Kosuru R, Cai Y, Kandula V, Yan D, Wang C, Zheng H, et al. (2018). AMPK Contributes to Cardioprotective Effects of Pterostilbene Against Myocardial Ischemia- Reperfusion Injury in Diabetic Rats by Suppressing Cardiac Oxidative Stress and Apoptosis. Cell Physiol Biochem, 46:1381-1397.
Kosuru R, Kandula V, Rai U, Prakash S, Xia Z, Singh S (2018). Pterostilbene Decreases Cardiac Oxidative Stress and Inflammation via Activation of AMPK/Nrf2/HO-1 Pathway in Fructose-Fed Diabetic Rats. Cardiovasc Drugs Ther, 32:147-163.
Guo S, Yao Q, Ke Z, Chen H, Wu J, Liu C (2015). Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK. Mol Cell Endocrinol, 412:85-94.
Elmore S (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol, 35:495-516.
Grilo AL, Mantalaris A (2019). Apoptosis: A mammalian cell bioprocessing perspective. Biotechnol Adv, 37:459-475.
Erekat NS2018. Apoptosis and its Role in Parkinson's Disease. In Parkinson's Disease: Pathogenesis and Clinical Aspects. Stoker TB, and Greenland JC, editors. Brisbane (AU).
Arguelles S, Guerrero-Castilla A, Cano M, Munoz MF, Ayala A (2019). Advantages and disadvantages of apoptosis in the aging process. Ann N Y Acad Sci, 1443:20-33.
Nakka VP, Gusain A, Mehta SL, Raghubir R (2008). Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol, 37:7-38.
Ichim G, Tait SW (2016). A fate worse than death: apoptosis as an oncogenic process. Nat Rev Cancer, 16:539-548.
Zhang Z, Wang S, Zhou S, Yan X, Wang Y, Chen J, et al. (2014). Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. J Mol Cell Cardiol, 77:42-52.
Zhang L, Ding WY, Wang ZH, Tang MX, Wang F, Li Y, et al. (2016). Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy. J Transl Med, 14:109.
Yeh CH, Chen TP, Wang YC, Lin YM, Fang SW (2010). AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress. Mediators Inflamm, 2010:130636.
Zhang GG, Cai HQ, Li YH, Sui YB, Zhang JS, Chang JR, et al. (2013). Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase. Peptides, 48:156-165.
Woehlbier U, Hetz C (2011). Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem Sci, 36:329-337.
Nam DH, Han JH, Kim S, Shin Y, Lim JH, Choi HC, et al. (2016). Activated protein C prevents methylglyoxal-induced endoplasmic reticulum stress and cardiomyocyte apoptosis via regulation of the AMP-activated protein kinase signaling pathway. Biochem Biophys Res Commun, 480:622-628.
Jung TW, Lee MW, Lee YJ, Kim SM (2012). Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway. Biochem Biophys Res Commun, 417:147-152.
Liu D, Ma Z, Di S, Yang Y, Yang J, Xu L, et al. (2018). AMPK/PGC1alpha activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. Free Radic Biol Med, 129:59-72.
Al-Damry NT, Attia HA, Al-Rasheed NM, Al-Rasheed NM, Mohamad RA, Al-Amin MA, et al. (2018). Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3beta and p38alpha/MAPK in a rat model of diabetic cardiomyopathy. Biomed Pharmacother, 107:347-358.
Moloudizargari M, Asghari MH, Ghobadi E, Fallah M, Rasouli S, Abdollahi M (2017). Autophagy, its mechanisms and regulation: Implications in neurodegenerative diseases. Ageing Res Rev, 40:64-74.
Mialet-Perez J, Vindis C (2017). Autophagy in health and disease: focus on the cardiovascular system. Essays Biochem, 61:721-732.
Saito T, Kuma A, Sugiura Y, Ichimura Y, Obata M, Kitamura H, et al. (2019). Autophagy regulates lipid metabolism through selective turnover of NCoR1. Nat Commun, 10:1567.
Zech ATL, Singh SR, Schlossarek S, Carrier L (2019). Autophagy in cardiomyopathies. Biochim Biophys Acta Mol Cell Res.
He C, Zhu H, Li H, Zou MH, Xie Z (2013). Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes, 62:1270-1281.
Zou MH, Xie Z (2013). Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy, 9:624-625.
Li RL, Wu SS, Wu Y, Wang XX, Chen HY, Xin JJ, et al. (2018). Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. J Mol Cell Cardiol, 121:242-255.
Alers S, Loffler AS, Wesselborg S, Stork B (2012). Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol, 32:2-11.
Takagi H, Matsui Y, Hirotani S, Sakoda H, Asano T, Sadoshima J (2007). AMPK mediates autophagy during myocardial ischemia in vivo. Autophagy, 3:405-407.
Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. (2007). Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res, 100:914-922.
Wang Y, Yang Z, Zheng G, Yu L, Yin Y, Mu N, et al. (2019). Metformin promotes autophagy in ischemia/reperfusion myocardium via cytoplasmic AMPKalpha1 and nuclear AMPKalpha2 pathways. Life Sci, 225:64-71.
Li C, Yu L, Xue H, Yang Z, Yin Y, Zhang B, et al. (2017). Nuclear AMPK regulated CARM1 stabilization impacts autophagy in aged heart. Biochem Biophys Res Commun, 486:398-405.
Wang S, Kandadi MR, Ren J (2019). Double knockout of Akt2 and AMPK predisposes cardiac aging without affecting lifespan: Role of autophagy and mitophagy. Biochim Biophys Acta Mol Basis Dis, 1865:1865-1875.
Ren J, Yang L, Zhu L, Xu X, Ceylan AF, Guo W, et al. (2017). Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1-mediated autophagy regulation. Aging Cell, 16:976-987.
Hua Y, Zhang Y, Ceylan-Isik AF, Wold LE, Nunn JM, Ren J (2011). Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res Cardiol, 106:1173-1191.
Zhang Y, Wang C, Zhou J, Sun A, Hueckstaedt LK, Ge J, et al. (2017). Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging. Biochim Biophys Acta Mol Basis Dis, 1863:1919-1932.
Medzhitov R (2008). Origin and physiological roles of inflammation. Nature, 454:428-435.
Kuprash DV, Nedospasov SA (2016). Molecular and Cellular Mechanisms of Inflammation. Biochemistry (Mosc), 81:1237-1239.
Chen X, Li X, Zhang W, He J, Xu B, Lei B, et al. (2018). Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-kappaB pathway. Metabolism, 83:256-270.
Wang X, Guo Z, Ding Z, Mehta JL (2018). Inflammation, Autophagy, and Apoptosis After Myocardial Infarction. J Am Heart Assoc, 7.
Ren J, Xu X, Wang Q, Ren SY, Dong M, Zhang Y (2016). Permissive role of AMPK and autophagy in adiponectin deficiency-accentuated myocardial injury and inflammation in endotoxemia. J Mol Cell Cardiol, 93:18-31.
Cieslik KA, Trial J, Entman ML (2017). Aicar treatment reduces interstitial fibrosis in aging mice: Suppression of the inflammatory fibroblast. J Mol Cell Cardiol, 111:81-85.
Xu X, Pang J, Chen Y, Bucala R, Zhang Y, Ren J (2016). Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation. Sci Rep, 6:22488.
Greco S, Gorospe M, Martelli F (2015). Noncoding RNA in age-related cardiovascular diseases. J Mol Cell Cardiol, 83:142-155.
Picca A, Mankowski RT, Burman JL, Donisi L, Kim JS, Marzetti E, et al. (2018). Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol, 15:543-554.
Gude NA, Broughton KM, Firouzi F, Sussman MA (2018). Cardiac ageing: extrinsic and intrinsic factors in cellular renewal and senescence. Nat Rev Cardiol, 15:523-542.
Costantino S, Paneni F, Cosentino F (2016). Ageing, metabolism and cardiovascular disease. J Physiol, 594:2061-2073.
Ding YN, Tang X, Chen HZ, Liu DP (2018). Epigenetic Regulation of Vascular Aging and Age-Related Vascular Diseases. Adv Exp Med Biol, 1086:55-75.
Ma H, Wang J, Thomas DP, Tong C, Leng L, Wang W, et al. (2010). Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart. Circulation, 122:282-292.
Chen Q, Lesnefsky EJ (2018). A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1. Cardiovasc Res, 114:771-772.
Abdellatif M, Sedej S, Carmona-Gutierrez D, Madeo F, Kroemer G (2018). Autophagy in Cardiovascular Aging. Circ Res, 123:803-824.
Favero G, Franceschetti L, Buffoli B, Moghadasian MH, Reiter RJ, Rodella LF, et al. (2017). Melatonin: Protection against age-related cardiac pathology. Ageing Res Rev, 35:336-349.
Kataoka Y, Shibata R, Ohashi K, Kambara T, Enomoto T, Uemura Y, et al. (2014). Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. J Am Coll Cardiol, 63:2722-2733.
Liu Z, Chen JM, Huang H, Kuznicki M, Zheng S, Sun W, et al. (2016). The protective effect of trimetazidine on myocardial ischemia/reperfusion injury through activating AMPK and ERK signaling pathway. Metabolism, 65:122-130.
Tian L, Cao W, Yue R, Yuan Y, Guo X, Qin D, et al. (2019). Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway. J Pharmacol Sci, 139:352-360.
Zhang Y, Wang Y, Xu J, Tian F, Hu S, Chen Y, et al. (2019). Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways. J Pineal Res, 66:e12542.
Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, et al. (2010). Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science, 327:1223-1228.
Quan N, Sun W, Wang L, Chen X, Bogan JS, Zhou X, et al. (2017). Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J, 31:4153-4167.
Liu Y, Zhao YB, Wang SW, Zhou Y, Tang ZS, Li F (2017). Mulberry granules protect against diabetic cardiomyopathy through the AMPK/Nrf2 pathway. Int J Mol Med, 40:913-921.
Sung MM, Zordoky BN, Bujak AL, Lally JS, Fung D, Young ME, et al. (2015). AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovasc Res, 107:235-245.
Dong HW, Zhang LF, Bao SL (2018). AMPK regulates energy metabolism through the SIRT1 signaling pathway to improve myocardial hypertrophy. Eur Rev Med Pharmacol Sci, 22:2757-2766.
Tang X, Chen XF, Wang NY, Wang XM, Liang ST, Zheng W, et al. (2017). SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy. Circulation, 136:2051-2067.
Alexanian M, Padmanabhan A, McKinsey TA, Haldar SM (2019). Epigenetic therapies in heart failure. J Mol Cell Cardiol, 130:197-204.
Gedela M, Khan M, Jonsson O (2015). Heart Failure. S D Med, 68:403-405, 407-409.
Li Y, Wang Y, Zou M, Chen C, Chen Y, Xue R, et al. (2018). AMPK blunts chronic heart failure by inhibiting autophagy. Biosci Rep, 38.
Li X, Liu J, Lu Q, Ren D, Sun X, Rousselle T, et al. (2019). AMPK: a therapeutic target of heart failure-not only metabolism regulation. Biosci Rep, 39.
Tanai E, Frantz S (2015). Pathophysiology of Heart Failure. Compr Physiol, 6:187-214.
Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, et al. (2007). Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest, 117:1782-1793.
Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, et al. (2003). Myocytes die by multiple mechanisms in failing human hearts. Circ Res, 92:715-724.
Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, et al. (2003). Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation, 107:984-991.
Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, et al. (2016). Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet, 387:239-250.
Li C, Sun W, Gu C, Yang Z, Quan N, Yang J, et al. (2018). Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility. Theranostics, 8:1027-1041.
Ma H, Li J, Gao F, Ren J (2009). Aldehyde dehydrogenase 2 ameliorates acute cardiac toxicity of ethanol: role of protein phosphatase and forkhead transcription factor. J Am Coll Cardiol, 54:2187-2196.
Ma H, Yu L, Byra EA, Hu N, Kitagawa K, Nakayama KI, et al. (2010). Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases. J Mol Cell Cardiol, 49:322-329.
Ma H, Guo R, Yu L, Zhang Y, Ren J (2011). Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde. Eur Heart J, 32:1025-1038.
Barzilai Nir,Appleby James C,Austad Steven N,Cuervo Ana Maria,Kaeberlein Matt,Gonzalez-Billault Christian,Lederman Stephanie,Stambler Ilia,Sierra Felipe. Geroscience in the Age of COVID-19[J]. Aging and disease, 2020, 11(4): 725-729.