Melatonin postconditioning combined with sitagliptin exerts full cardioprotection in diabetic hearts of aged rats through an AMPK-dependent mechanism


  • Ronggang Song Department of Cardiology, The Fifth People's Hospital of Jinan, Jinan, Shandong, 250022
  • Jing Ren Binzhou Youfu Hospital, Changjiang Yi Lu, Binzhou, Shandong, 256600
  • Junxia Sun Binzhou Youfu Hospital, Changjiang Yi Lu, Binzhou, Shandong, 256600
  • Ming Li Department of Cardiology, The Fifth People's Hospital of Jinan, Jinan, Shandong, 250022



Diabetes, cardioprotection, aging, AMPK, postconditioning, melatonin, DPP-4


Paper description:

  • Cardioprotection in diabetic elderly patients requires effective combinational therapies.
  • This study investigated the effect of melatonin postconditioning combined with sitagliptin pretreatment on myocardial ischemia-reperfusion (IR) injury in diabetic aged rats.
  • Combination therapy with melatonin and sitagliptin was superior to individual interventions in limiting infarct size in type-2 diabetic aged rats after IR injury as a result of suppression of mitochondrial-dependent oxidative stress and apoptosis.
  • Cardioprotective effects of combination therapy were accomplished by activating the AMPK/SIRT1 pathway.
  • Combined use of melatonin and sitagliptin is a potentially promising strategy for treating elderly diabetic patients with ischemic heart disease.

Abstract: The presence of multiple comorbidities in patients facing myocardial ischemia-reperfusion (IR) injury is the main obstacle for cardioprotection. This study investigated the effect of melatonin postconditioning combined with sitagliptin pretreatment on cardioprotection in diabetic aged rats by evaluating oxidative stress, apoptosis and involvement of the AMPK/SIRT1 pathway. The type-2 high-fat/streptozotocin experimental model in aged Sprague-Dawley rats (n=78) was used. The animals underwent left coronary occlusion for 30 min, followed by 3 h reperfusion. Diabetic rats were pretreated with sitagliptin (20 mg/kg, i.p.) and received melatonin (10 mg/kg, i.p.) early in reperfusion. Myocardial infarct size, histological changes, oxidative markers, mitochondrial reactive oxygen species (mitoROS) and expression of proteins regulating apoptosis and AMPK/SIRT1 activity were measured. The infarct size-sparing effect of the combination of melatonin plus sitagliptin was greater than that observed in individual treatments (P<0.01). Combination therapy significantly reduced IR-induced elevation of 8-isoprostane, mitoROS and proapoptotic proteins Bax and cleaved caspase-3, and increased IR-induced downregulation of mitochondrial superoxide-dismutase, glutathione, anti-apoptotic protein Bcl2, phosphorylated AMPK and SIRT1 (P<0.01, P<0.001). Inhibition of AMPK via compound-C completely reversed combination-induced cardioprotection. Thus, improving cardiac antioxidative and antiapoptotic responses via upregulation of AMPK/SIRT1 activity may represent a central mechanism through which melatonin plus sitagliptin attenuate myocardial IR injury in diabetic-aged rats.


Download data is not yet available.


Li H, Liu Z, Wang J, Wong GT, Cheung C-W, Zhang L, Chen C, Xia Z, Irwin MG. Susceptibility to myocardial ischemia reperfusion injury at early stage of type 1 diabetes in rats. Cardiovasc Diabetol. 2013;12:133.

Al-Nozha MM, Ismail HM, Al Nozha OM. Coronary artery disease and diabetes mellitus. J Taibah University Med Sci. 2016;11:330-8.

Yao W, Tai LW, Liu Y, Hei Z, Li H. Oxidative Stress and Inflammation Interaction in Ischemia Reperfusion Injury: Role of Programmed Cell Death. Oxid Med Cell Longev. 2019;2019:6780816.

Bozkurt B, Aguilar D, Deswal A, Dunbar Sandra B, Francis Gary S, Horwich T, Jessup M, Kosiborod M, Pritchett Allison M, Ramasubbu K, Rosendorff C, Yancy C. Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016;134:e535-e578.

Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica et Biophysica Acta (BBA). Mol Cell Res. 2016;1863:2977-92.

Pereira AS, Gouveia AM, Tomada N, Rodrigues AR, Neves D. Cumulative Effect of Cardiovascular Risk Factors on Regulation of AMPK/SIRT1-PGC-1α-SIRT3 Pathway in the Human Erectile Tissue. Oxid Med Cell Longev. 2020;2020:1525949.

Jeon S-M. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48:e245-e245.

Timm KN, Tyler DJ. The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity. Cardiovasc Drugs Ther. 2020;34:255-69.

Potenza MA, Sgarra L, Nacci C, Leo V, De Salvia MA, Montagnani M. Activation of AMPK/SIRT1 axis is required for adiponectin-mediated preconditioning on myocardial ischemia-reperfusion (I/R) injury in rats. PLOS ONE. 2019;14:e0210654.

Patel R, Pramanik S, Rathwa Nn, Parmar Nr, Dhimmar H, Pancholi Da, Begum R. Melatonin and DPP-IV Inhibitor: A Novel Combinatorial Approach for ß-Cell Regeneration. Diabetes. 2019;68:112-LB.

Forrestel AC, Miedlich SU, Yurcheshen M, Wittlin SD, Sellix MT. Chronomedicine and type 2 diabetes: shining some light on melatonin. Diabetologia. 2017;60:808-22.

Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175:3190-9.

Imenshahidi M, Karimi G, Hosseinzadeh H. Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review. Naunyn-Schmiedeberg's Arch Pharmacol. 2020;393:521-36.

Jiki Z, Lecour S, Nduhirabandi F. Cardiovascular Benefits of Dietary Melatonin: A Myth or a Reality? Front Physiol. 2018;9:528.

Gul-Kahraman K, Yilmaz-Bozoglan M, Sahna E. Physiological and pharmacological effects of melatonin on remote ischemic perconditioning after myocardial ischemia-reperfusion injury in rats: Role of Cybb, Fas, NfκB, Irisin signaling pathway. J Pineal Res. 2019;67:e12589.

Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, Mu Y. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47:2067-76.

El-Agamy DS, Abo-Haded HM, Elkablawy MA. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Exp Biol Med (Maywood). 2016;241:1577-87.

Nakamura T, Iwanaga Y, Miyaji Y, Nohara R, Ishimura T, Miyazaki S. On behalf of the Sitagliptin Registry Kinki Cardiologists’ Study I. Cardiovascular efficacy of sitagliptin in patients with diabetes at high risk of cardiovascular disease: a 12-month follow-up. Cardiovasc Diabetol. 2016;15:54.

Kamble HV, Bodhankar SL. Cardioprotective effect of concomitant administration of trigonelline and sitagliptin on cardiac biomarkers, lipid levels, electrocardiographic and haemodynamic modulation on cardiomyopathy in diabetic Wistar rats. Biomed Aging Pathol. 2014;4:335-42.

Nauck MA, McGuire DK, Pieper KS, Lokhnygina Y, Strandberg TE, Riefflin A, Delibasi T, Peterson ED, White HD, Scott R, Holman RR. Sitagliptin does not reduce the risk of cardiovascular death or hospitalization for heart failure following myocardial infarction in patients with diabetes: observations from TECOS. Cardiovasc Diabetol. 2019;18:116.

Zhang M, Lv XY, Li J, Xu ZG, Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res. 2008;2008:704045.

Shi S, Lei S, Tang C, Wang K, Xia Z. Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway. Biosci Rep. 2019;39(1):BSR20181614.

Hong L, Sun Y, An J-Z, Wang C, Qiao S-G. Sevoflurane Preconditioning Confers Delayed Cardioprotection by Upregulating AMP-Activated Protein Kinase Levels to Restore Autophagic Flux in Ischemia-Reperfusion Rat Hearts. Med Sci Mon Int Med J Exp Clin Res. 2020;26:e922176-e922176.

Xia Z, Li H, Irwin MG. Myocardial ischaemia reperfusion injury: the challenge of translating ischaemic and anaesthetic protection from animal models to humans. Br J Anaesth. 2016;117:ii44-ii62.

Reiter RJ, Mayo JC, Tan D-X, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61:253-78.

Prakash S, Rai U, Uniyal A, Tiwari V, Singh S. Sitagliptin mitigates oxidative stress and up-regulates mitochondrial biogenesis markers in Brown adipose tissues of high-fat diet fed obese mice through AMPK phosphorylation. Obes Med. 2020;19:100265.

Wang Y-P, Lei Q-Y. Metabolite sensing and signaling in cell metabolism. Signal Transduct Target Ther. 2018;3:30.

Athithan L, Gulsin GS, McCann GP, Levelt E. Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date. World J Diabetes. 2019;10:490-510.

Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol. 2014;2:702-14.

Ruderman NB, Julia Xu X, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298:E751-E760.

Qi D, Young LH. AMPK: energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol. Metab. 2015;26:422-9.

Rius-Pérez S, Torres-Cuevas I, Millán I, Ortega ÁL, Pérez S. PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. Oxid Med Cell Longev. 2020;2020:1452696.

Zhou Y, Guo Z, Yan W, Wang W. Cardiovascular effects of sitagliptin – An anti-diabetes medicine. Clin Exp Pharmacol Physiol. 2018;45:628-35.

Yu LM, Di WC, Dong X, Li Z, Zhang Y, Xue XD, Xu YL, Zhang J, Xiao X, Han JS, Liu Y, Yang Y, Wang HS. Melatonin protects diabetic heart against ischemia-reperfusion injury, role of membrane receptor-dependent cGMP-PKG activation. Biochim Biophys Acta Mol Basis Dis. 2018;1864:563-78.




How to Cite

Song R, Ren J, Sun J, Li M. Melatonin postconditioning combined with sitagliptin exerts full cardioprotection in diabetic hearts of aged rats through an AMPK-dependent mechanism. Arch Biol Sci [Internet]. 2021Mar.19 [cited 2022Aug.9];73(1):83-92. Available from: