Emerging role of melatonin in the alleviation of ischemic heart disease: A comprehensive review
Article Sidebar
Main Article Content
Abstract
Melatonin, a circardian biomolecule exerts cardioprotective effects through its ability to directly scavenge free radicals and to indirectly act as an antioxidant. It has biological functions such as anti-apoptosis, anti-inflammation, antioxidant activity, mitochondrial protection, and controlling the production of cytokines by target cells. Melatonin also showed blood pressure lowering, normalising lipid profiles, and anti-inflammatory characteristics. Melatonin plays critical roles in averting oxidative stress, enhancing autophagic cell repair, modulating immunological and inflammatory responses, improving mitochondrial function, and reducing endoplasmic reticulum stress in cardiomyocytes. The absence of these cardioprotective properties due to low melatonin levels may be linked to an array of cardiovascular diseases, including ischemic heart disease. As a result, administration of melatonin is anticipated to have a clinically important role in the management of ischemic heart disease; an assertion backed by melatonin's low toxicity and high safety. Therefore, the evidence gathered in this review should provide comprehensive information on melatonin's effect in cardioprotection and, perhaps, contribute to the planning of future experimental studies.
Article Details
References
REFERENCES
North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res. 2012;110(8):1097-1108. doi:10.1161/CIRCRESAHA.111.246876
Stenling A, Häggström C, Norberg M, Norström F. Lifetime risk predictions for cardiovascular diseases: Competing risks analyses on a population-based cohort in Sweden. Atherosclerosis. 2020;312:90-98. doi:10.1016/j.atherosclerosis.2020.08.014
Maleki B, Alani B, Tamehri Zadeh SS, et al. MicroRNAs and exosomes: Cardiac stem cells in heart diseases. Pathol Res Pract. 2022;229:153701. doi:10.1016/j.prp.2021.153701
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117-171. doi:10.1016/S0140-6736(14)61682-2
Sajjadieh Khajouei A, Adibi A, Maghsodi Z, Nejati M, Behjati M. Prognostic value of normal and non-obstructive coronary artery disease based on CT angiography findings. A 12 month follow up study. J Cardiovasc Thorac Res. 2019;11(4):318-321. doi:10.15171/jcvtr.2019.52
Mendis, Shanthi, Puska, Pekka, Norrving, B, World Health Organization, World Heart Federation. et al. Global atlas on cardiovascular disease prevention and control. World Health Organization. 2011.https://apps.who.int/iris/handle/10665/44701
Khosravi, A., Bideh, F. Z., Roghani, F., Saadatnia, M., Khorvash, F., Nejati, M., Khoshpour, N., & Behjati, M. (2018). Carotid arterial stent implantation follow-up and results in 50 patients: preliminary report. Electronic physician, 10(2), 6400–6405. https://doi.org/10.19082/6400
S. Sans, H. Kesteloot, D. Kromhout, The burden of cardiovascular diseases mortality in Europe: Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe, European Heart Journal, Volume 18, Issue 8, August 1997, Pages 1231–1248, https://doi.org/10.1093/oxfordjournals.eurheartj.a015434
Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of coronary heart disease in low- and middle-income countries. Curr Probl Cardiol. 2010;35(2):72-115. doi:10.1016/j.cpcardiol.2009.10.002
Akhtar S. Ischemic heart disease. Anesthesiol Clin. 2006;24(3):461-485. doi:10.1016/j.atc.2006.04.002
Mozos I. Links between shift work, cardiovascular risk and disorders. In: He W, Yu L, editors. Shift Work: Impacts, Disorders and Studies. New York: Nova Science Pub Inc; 2017. pp. 23-44
Davidson SM, Ferdinandy P, Andreadou I, et al. Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;73(1):89-99. doi:10.1016/j.jacc.2018.09.086
Heusch G. Cardioprotection research must leave its comfort zone. Eur Heart J. 2018;39(36):3393-3395. doi:10.1093/eurheartj/ehy253
Masui, K., Oguchi, T., Kashimoto, S., Yamaguchi, T., Kumazawa, T. (2000). Effects of Melatonin on Cardiac Function and Metabolism in the Ischemic Working Rat Heart. In: Takeda, N., Nagano, M., Dhalla, N.S. (eds) The Hypertrophied Heart. Progress in Experimental Cardiology. Springer, Boston, MA. 2000;3. https://doi.org/10.1007/978-1-4615-4423-4_37
Paulis L, Simko F, Laudon M. Cardiovascular effects of melatonin receptor agonists. Expert Opin Investig Drugs. 2012;21(11):1661-1678. doi:10.1517/13543784.2012.714771
Galano A, Reiter RJ. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J Pineal Res. 2018;65(1):e12514. doi:10.1111/jpi.12514
Acuña-Castroviejo D, Escames G, Venegas C, et al. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014;71(16):2997-3025. doi:10.1007/s00018-014-1579-2
Zawilska JB, Skene DJ, Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep. 2009;61(3):383-410. doi:10.1016/s1734-1140(09)70081-7
Reiter RJ, Tan DX, Galano A. Melatonin: exceeding expectations. Physiology (Bethesda). 2014;29(5):325-333. doi:10.1152/physiol.00011.2014
Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin--a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011;93(3):350-384. doi:10.1016/j.pneurobio.2010.12.004
Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet. 1995;345(8962):1408. doi:10.1016/s0140-6736(95)92600-3
Fiorina P, Lattuada G, Ponari O, Silvestrini C, DallAglio P. Impaired nocturnal melatonin excretion and changes of immunological status in ischaemic stroke patients. Lancet. 1996;347(9002):692-693. doi:10.1016/s0140-6736(96)91246-5
Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons [published correction appears in Circulation. 2014 Apr 22;129(16):e463]. Circulation. 2012;126(25):e354-e471. doi:10.1161/CIR.0b013e318277d6a0
Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes [published correction appears in Eur Heart J. 2020 Nov 21;41(44):4242]. Eur Heart J. 2020;41(3):407-477. doi:10.1093/eurheartj/ehz425
Libby P, Pasterkamp G, Crea F, Jang IK. Reassessing the Mechanisms of Acute Coronary Syndromes. Circ Res. 2019;124(1):150-160. doi:10.1161/CIRCRESAHA.118.311098
Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Glob Heart. 2018;13(4):305-338. doi:10.1016/j.gheart.2018.08.004
Datta, M., Majumder, R., Chattopadhyay, A. and Bandyopadhyay, D. Protective effect of melatonin in atherosclerotic cardiovascular disease: A comprehensive review. Melatonin Research. 2021 Sep;4(3):408-430. DOI:https://doi.org/https://doi.org/10.32794/mr112500102.
Pepine CJ, Nichols WW. The pathophysiology of chronic ischemic heart disease. Clin Cardiol. 2007;30(2 Suppl 1):I4-I9. doi:10.1002/clc.20048
Schoenhagen P, Ziada KM, Vince DG, Nissen SE, Tuzcu EM. Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis. J Am Coll Cardiol. 2001;38(2):297-306. doi:10.1016/s0735-1097(01)01374-2
Huang Y, Hickey RP, Yeh JL, et al. Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J. 2004;18(10):1138-1140. doi:10.1096/fj.04-1510fje
Davies KJ. Oxidative stress: the paradox of aerobic life. Biochem Soc Symp. 1995;61:1-31. doi:10.1042/bss0610001
Albakri A. Ischemic heart failure: A review of clinical status and meta-analysis of diagnosis and clinical management methods. St-Marien hospital Bonn Venusberg, department of internal medicine, Bonn, Germany. Clin Med Invest, 2018;3(4):1-15.doi: 10.15761/CMI.1000171
Li Q, Turdi S, Thomas DP, Zhou T, Ren J. Intra-myocardial delivery of mesenchymal stem cells ameliorates left ventricular and cardiomyocyte contractile dysfunction following myocardial infarction. Toxicol Lett. 2010;195(2-3):119-126. doi:10.1016/j.toxlet.2010.03.009
Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. doi:10.1038/s41418-017-0012-4
Abukar Y, Ramchandra R, Hood SG, et al. Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis. Basic Res Cardiol. 2018;113(5):35. Published 2018 Aug 3. doi:10.1007/s00395-018-0695-9
Beckendorf J, van den Hoogenhof MMG, Backs J. Physiological and unappreciated roles of CaMKII in the heart. Basic Res Cardiol. 2018;113(4):29. Published 2018 Jun 15. doi:10.1007/s00395-018-0688-8
Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y. Protective role of melatonin in cardiac ischemia-reperfusion injury: From pathogenesis to targeted therapy. J Pineal Res. 2018;64(3):10.1111/jpi.12471. doi:10.1111/jpi.12471
Hu C, Zhang X, Wei W, et al. Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway. Acta Pharm Sin B. 2019;9(4):690-701. doi:10.1016/j.apsb.2019.03.003
Zhang Y, Mi SL, Hu N, et al. Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. Free Radic Biol Med. 2014;71:208-220. doi:10.1016/j.freeradbiomed.2014.03.018
Joshi C, Bapat R, Anderson W, Dawson D, Hijazi K, Cherukara G. Detection of periodontal microorganisms in coronary atheromatous plaque specimens of myocardial infarction patients: A systematic review and meta-analysis. Trends Cardiovasc Med. 2021;31(1):69-82. doi:10.1016/j.tcm.2019.12.005
Zhou H, Wang J, Zhu P, et al. NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol. 2018;113(4):23. Published 2018 May 9. doi:10.1007/s00395-018-0682-1
Zhou H, Wang J, Zhu P, et al. NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol. 2018;113(4):23. Published 2018 May 9. doi:10.1007/s00395-018-0682-1
Jensen RV, Hjortbak MV, Bøtker HE. Ischemic Heart Disease: An Update. Semin Nucl Med. 2020;50(3):195-207. doi:10.1053/j.semnuclmed.2020.02.007
Braunwald E. Coronary-artery surgery at the crossroads. N Engl J Med. 1977;297(12):661-663. doi:10.1056/NEJM197709222971209
Stone GW, Hochman JS, Williams DO, et al. Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise. J Am Coll Cardiol. 2016;67(1):81-99. doi:10.1016/j.jacc.2015.09.056
Chacko L, P Howard J, Rajkumar C, et al. Effects of Percutaneous Coronary Intervention on Death and Myocardial Infarction Stratified by Stable and Unstable Coronary Artery Disease: A Meta-Analysis of Randomized Controlled Trials. Circ Cardiovasc Qual Outcomes. 2020;13(2):e006363. doi:10.1161/CIRCOUTCOMES.119.006363
Severino P, D'Amato A, Pucci M, et al. Ischemic Heart Disease Pathophysiology Paradigms Overview: From Plaque Activation to Microvascular Dysfunction. Int J Mol Sci. 2020;21(21):8118. Published 2020 Oct 30. doi:10.3390/ijms21218118
Kibel A, Lukinac AM, Dambic V, Juric I, Selthofer-Relatic K. Oxidative Stress in Ischemic Heart Disease. Oxid Med Cell Longev. 2020;2020:6627144. Published 2020 Dec 28. doi:10.1155/2020/6627144
Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000;87(10):840-844. doi:10.1161/01.res.87.10.840
Förstermann U, Xia N, Li H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ Res. 2017;120(4):713-735. doi:10.1161/CIRCRESAHA.116.309326
Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459(6):923-939. doi:10.1007/s00424-010-0808-2
Yeh HL, Kuo LT, Sung FC, Yeh CC. Association between Polymorphisms of Antioxidant Gene (MnSOD, CAT, and GPx1) and Risk of Coronary Artery Disease. Biomed Res Int. 2018;2018:5086869. Published 2018 Aug 26. doi:10.1155/2018/5086869
Tibaut M, Petrovič D. Oxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus. Cardiovasc Hematol Agents Med Chem. 2016;14(1):23-38. doi:10.2174/1871525714666160407143416.
Mercer JR, Yu E, Figg N, et al. The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice. Free Radic Biol Med. 2012;52(5):841-849. doi:10.1016/j.freeradbiomed.2011.11.026
Wang Y, Li L, Zhao W, et al. Targeted Therapy of Atherosclerosis by a Broad-Spectrum Reactive Oxygen Species Scavenging Nanoparticle with Intrinsic Anti-inflammatory Activity. ACS Nano. 2018;12(9):8943-8960. doi:10.1021/acsnano.8b02037
Gimbrone MA Jr, García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol. 2013;22(1):9-15. doi:10.1016/j.carpath.2012.06.006
Leopold JA, Loscalzo J. Oxidative risk for atherothrombotic cardiovascular disease. Free Radic Biol Med. 2009;47(12):1673-1706. doi:10.1016/j.freeradbiomed.2009.09.009
Gramlich Y, Daiber A, Buschmann K, et al. Oxidative Stress in Cardiac Tissue of Patients Undergoing Coronary Artery Bypass Graft Surgery: The Effects of Overweight and Obesity. Oxid Med Cell Longev. 2018;2018:6598326. Published 2018 Dec 17. doi:10.1155/2018/6598326
Seimon TA, Nadolski MJ, Liao X, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12(5):467-482. doi:10.1016/j.cmet.2010.09.010
Barbosa JE, Stockler-Pinto MB, Cruz BOD, et al. Nrf2, NF-κB and PPARβ/δ mRNA Expression Profile in Patients with Coronary Artery Disease. Arq Bras Cardiol. 2019;113(6):1121-1127. doi:10.5935/abc.20190125
Mozzini C, Fratta Pasini A, Garbin U, et al. Increased endoplasmic reticulum stress and Nrf2 repression in peripheral blood mononuclear cells of patients with stable coronary artery disease. Free Radic Biol Med. 2014;68:178-185. doi:10.1016/j.freeradbiomed.2013.12.017
Zhu H, Jia Z, Zhang L, et al. Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress. Exp Biol Med (Maywood). 2008;233(4):463-474. doi:10.3181/0711-RM-304
Collins AJ, Foley RN, Chavers B, et al. 'United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis. 2012;59(1 Suppl 1):A7-e420. doi:10.1053/j.ajkd.2011.11.015
Visvikis-Siest S, Marteau JB, Samara A, Berrahmoune H, Marie B, Pfister M. Peripheral blood mononuclear cells (PBMCs): a possible model for studying cardiovascular biology systems. Clin Chem Lab Med. 2007;45(9):1154-1168. doi:10.1515/CCLM.2007.255
Xiao Y, Xia J, Cheng J, et al. Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway. Circulation. 2019;139(19):2260-2277. doi:10.1161/CIRCULATIONAHA.118.036336
Chan SH, Hung CH, Shih JY, et al. SIRT1 inhibition causes oxidative stress and inflammation in patients with coronary artery disease. Redox Biol. 2017;13:301-309. doi:10.1016/j.redox.2017.05.027
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239-257. doi:10.1038/bjc.1972.33
Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM. Apoptosis in human acute myocardial infarction. Circulation. 1997;95(2):320-323. doi:10.1161/01.cir.95.2.320
Olivetti G, Quaini F, Sala R, et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1996;28(9):2005-2016. doi:10.1006/jmcc.1996.0193
Abbate A, Melfi R, Patti G, et al. Apoptosis in recent myocardial infarction. Clin Ter. 2000;151(4):247-251.
Abbate A, Biondi-Zoccai GG, Bussani R, et al. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure. J Am Coll Cardiol. 2003;41(5):753-760. doi:10.1016/s0735-1097(02)02959-5
Baldi A, Abbate A, Bussani R, et al. Apoptosis and post-infarction left ventricular remodeling. J Mol Cell Cardiol. 2002;34(2):165-174. doi:10.1006/jmcc.2001.1498
Krown KA, Page MT, Nguyen C, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest. 1996;98(12):2854-2865. doi:10.1172/JCI119114
Asgeri M, Pourafkari L, Kundra A, Javadzadegan H, Negargar S, Nader ND. Dual effects of tumor necrosis factor alpha on myocardial injury following prolonged hypoperfusion of the heart. Immunol Invest. 2015;44(1):23-35. doi:10.3109/08820139.2014.921689
Doyama K, Fujiwara H, Fukumoto M, et al. Tumour necrosis factor is expressed in cardiac tissues of patients with heart failure. Int J Cardiol. 1996;54(3):217-225. doi:10.1016/0167-5273(96)02607-1
Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93(4):704-711. doi:10.1161/01.cir.93.4.704
Brocheriou V, Hagège AA, Oubenaïssa A, et al. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med. 2000;2(5):326-333. doi:10.1002/1521-2254(200009/10)2:5<326::AID-JGM133>3.0.CO;2-1
Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol. 2001;280(5):H2313-H2320. doi:10.1152/ajpheart.2001.280.5.H2313
Misao J, Hayakawa Y, Ohno M, Kato S, Fujiwara T, Fujiwara H. Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation. 1996;94(7):1506-1512. doi:10.1161/01.cir.94.7.1506
Condorelli G, Roncarati R, Ross J Jr, et al. Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function. Proc Natl Acad Sci U S A. 2001;98(17):9977-9982. doi:10.1073/pnas.161120198
Liu Q. Lentivirus mediated interference of Caspase-3 expression ameliorates the heart function on rats with acute myocardial infarction. Eur Rev Med Pharmacol Sci. 2014;18(13):1852-1858. PMID: 25010613
Aaron B. Lerner, James D. Case, and Richard V. STRUCTURE OF MELATONIN.Heinzelman Journal of the American Chemical Society 1959 81 (22), 6084-6085 DOI: 10.1021/ja01531a060
Cipolla-Neto J, Amaral FGD. Melatonin as a Hormone: New Physiological and Clinical Insights. Endocr Rev. 2018;39(6):990-1028. doi:10.1210/er.2018-00084
Canteras NS, Ribeiro-Barbosa ER, Goto M, Cipolla-Neto J, Swanson LW. The retinohypothalamic tract: comparison of axonal projection patterns from four major targets. Brain Res Rev. 2011;65(2):150-183. doi:10.1016/j.brainresrev.2010.09.006
Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol. 2018;175(16):3263-3280. doi:10.1111/bph.13950
Kurhaluk N, Bojkova B, Radkowski M, et al. Melatonin and Metformin Diminish Oxidative Stress in Heart Tissue in a Rat Model of High Fat Diet and Mammary Carcinogenesis. Adv Exp Med Biol. 2018;1047:7-19. doi:10.1007/5584_2017_128
Gerush IV, Bevzo VV, Ferenchuk YO. The effect of melatonin on lipid peroxide oxidation, oxidative modification of proteins and mitochondria swelling in the skeletal muscle tissue of rats under alloxan diabetes. Ukrainian Biochemical Journal. 2018;90:62-69. doi: https://doi.org/10.15407/ubj90.03.062
Djordjevic B, Cvetkovic T, Stoimenov TJ, et al. Oral supplementation with melatonin reduces oxidative damage and concentrations of inducible nitric oxide synthase, VEGF and matrix metalloproteinase 9 in the retina of rats with streptozotocin/nicotinamide induced pre-diabetes. Eur J Pharmacol. 2018;833:290-297. doi:10.1016/j.ejphar.2018.06.011
Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2019;38(1):191-196. doi:10.1016/j.clnu.2017.12.004
Kara, H., & Kara, A. Melatonin in Cardiovascular Diseases. Melatonin - Recent Updates. 2022. doi: 10.5772/intechopen.106085
Nosjean O, Ferro M, Coge F, et al. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem. 2000;275(40):31311-31317. doi:10.1074/jbc.M005141200
Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ. Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism. Molecules. 2015;20(10):18886-18906. Published 2015 Oct 16. doi:10.3390/molecules201018886
Jockers R, Delagrange P, Dubocovich ML, et al. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol. 2016;173(18):2702-2725. doi:10.1111/bph.13536
Acuña-Castroviejo D, Escames G, Venegas C, et al. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014;71(16):2997-3025. doi:10.1007/s00018-014-1579-2
Vandewalle G, Middleton B, Rajaratnam SM, et al. Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod. J Sleep Res. 2007;16(2):148-155. doi:10.1111/j.1365-2869.2007.00581.x
Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43(2):192-197. doi:10.1161/01.HYP.0000113293.15186.3b
Scheer FA. Potential use of melatonin as adjunct antihypertensive therapy. Am J Hypertens. 2005;18(12 Pt 1):1619-1620. doi:10.1016/j.amjhyper.2005.07.013
Tobeiha M, Jafari A, Fadaei S, et al. Evidence for the Benefits of Melatonin in Cardiovascular Disease. Front Cardiovasc Med. 2022;9:888319. Published 2022 Jun 20. doi:10.3389/fcvm.2022.888319
Nduhirabandi F, du Toit EF, Lochner A. Melatonin and the metabolic syndrome: a tool for effective therapy in obesity-associated abnormalities?. Acta Physiol (Oxf). 2012;205(2):209-223. doi:10.1111/j.1748-1716.2012.02410.x
Sewerynek E. Melatonin and the cardiovascular system. Neuro Endocrinol Lett. 2002;23 Suppl 1:79-83. PMID: 12019357
Pechanova O, Paulis L, Simko F. Peripheral and central effects of melatonin on blood pressure regulation. Int J Mol Sci. 2014;15(10):17920-17937. Published 2014 Oct 8. doi:10.3390/ijms151017920
Sarkar S, Chattopadhyay A,Bandyopadhyay D. Multiple strategies of melatonin protecting against cardiovascular injury related to inflammation: a comprehensive overview. Melatonin Res. 2021; 4:1-29. DOI:https://doi.org/https://doi.org/10.32794/mr11250080.
Nikolaev G, Robeva R, Konakchieva R. Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease. Int J Mol Sci. 2021;23(1):471. Published 2021 Dec 31. doi:10.3390/ijms23010471
Lochner A, Huisamen B, Nduhirabandi F. Cardioprotective effect of melatonin against ischaemia/reperfusion damage. Front Biosci (Elite Ed). 2013;5(1):305-315. Published 2013 Jan 1. doi:10.2741/e617
Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Med Rev. 2005;9(1):25-39. doi:10.1016/j.smrv.2004.05.002
Baker J, Kimpinski K. Role of melatonin in blood pressure regulation: An adjunct anti-hypertensive agent. Clin Exp Pharmacol Physiol. 2018;45(8):755-766. doi:10.1111/1440-1681.12942
Zanoboni A, Forni A, Zanoboni-Muciaccia W, Zanussi C. Effect of pinealectomy on arterial blood pressure and food and water intake in the rat. J Endocrinol Invest. 1978;1(2):125-130. doi:10.1007/BF03350359
Maarman G, Blackhurst D, Thienemann F, et al. Melatonin as a preventive and curative therapy against pulmonary hypertension. J Pineal Res. 2015;59(3):343-353. doi:10.1111/jpi.12263
Zhao Y, Xu L, Ding S, et al. Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy. J Pineal Res. 2017;62(3):10.1111/jpi.12378. doi:10.1111/jpi.12378
Zhou H, Yue Y, Wang J, Ma Q, Chen Y. Melatonin therapy for diabetic cardiomyopathy: A mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal. 2018;47:88-100. doi:10.1016/j.cellsig.2018.03.012
Uchinaka A, Kawashima Y, Sano Y, et al. Effects of ramelteon on cardiac injury and adipose tissue pathology in rats with metabolic syndrome. Ann N Y Acad Sci. 2018;1421(1):73-87. doi:10.1111/nyas.13578
Yeung HM, Hung MW, Lau CF, Fung ML. Cardioprotective effects of melatonin against myocardial injuries induced by chronic intermittent hypoxia in rats. J Pineal Res. 2015;58(1):12-25. doi:10.1111/jpi.12190
Sarkar, S., Chattopadhyay, A. and Bandyopadhyay, D. 2021. Melatonin as a prospective metabolic regulator in pathologically altered cardiac energy homeostasis. Melatonin Research. 2021 Apr;4(2):316-335. DOI:https://doi.org/https://doi.org/10.32794/mr11250097.
Mukherjee D, Ghosh AK, Bandyopadhyay A, Basu A, Datta S, Pattari SK, Reiter RJ, Bandyopadhyay D. Melatonin protects against isoproterenol-induced alterations in cardiac mitochondrial energy-metabolizing enzymes, apoptotic proteins, and assists in complete recovery from myocardial injury in rats. J. Pineal Res. 2012;53(2):166-179. https://doi.org/10.1111/j.1600-079X.2012.00984.x.
Mukherjee D, Ghosh AK, Dutta M, Mitra E, Mallick S, Saha B, Reiter RJ, Bandyopadhyay D . Mechanisms of isoproterenol-induced cardiac mitochondrial damage: protective actions of melatonin. J. Pineal Res. 2015; 58(3):275-290. doi: 10.1111/jpi.12213.
Xie S, Deng Y, Pan YY, et al. Melatonin protects against chronic intermittent hypoxia-induced cardiac hypertrophy by modulating autophagy through the 5' adenosine monophosphate-activated protein kinase pathway. Biochem Biophys Res Commun. 2015;464(4):975-981. doi:10.1016/j.bbrc.2015.06.1498
Datta, M., Majumder, R., Chattopadhyay, A. and Bandyopadhyay, D. 2022. Melatonin as a protective adjunct to the renin angiotensin system imbalance induced cardiovascular pathogenesis: A review. Melatonin Research. Jun;5(2):154-170. DOI:https://doi.org/https://doi.org/10.32794/mr112500126.
Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J Pineal Res. 2013;54(3):245-257. doi:10.1111/jpi.12010
Yang Y, Sun Y, Yi W, et al. A review of melatonin as a suitable antioxidant against myocardial ischemia-reperfusion injury and clinical heart diseases. J Pineal Res. 2014;57(4):357-366. doi:10.1111/jpi.12175
Diez ER, Prados LV, Carrión A, Ponce ZA, Miatello RM. A novel electrophysiologic effect of melatonin on ischemia/reperfusion-induced arrhythmias in isolated rat hearts. J Pineal Res. 2009;46(2):155-160. doi:10.1111/j.1600-079X.2008.00643.x
Yeung HM, Hung MW, Fung ML. Melatonin ameliorates calcium homeostasis in myocardial and ischemia-reperfusion injury in chronically hypoxic rats. J Pineal Res. 2008;45(4):373-382. doi:10.1111/j.1600-079X.2008.00601.x
Genade S, Genis A, Ytrehus K, Huisamen B, Lochner A. Melatonin receptor-mediated protection against myocardial ischaemia/reperfusion injury: role of its anti-adrenergic actions. J Pineal Res. 2008;45(4):449-458. doi:10.1111/j.1600-079X.2008.00615.x
Mahal HS, Sharma HS, Mukherjee T. Antioxidant properties of melatonin: a pulse radiolysis study. Free Radic Biol Med. 1999;26(5-6):557-565. doi:10.1016/s0891-5849(98)00226-3
Blanchard B, Pompon D, Ducrocq C. Nitrosation of melatonin by nitric oxide and peroxynitrite. J Pineal Res. 2000;29(3):184-192. doi:10.1034/j.1600-079x.2000.290308.x
Choi SI, Joo SS, Yoo YM. Melatonin prevents nitric oxide-induced apoptosis by increasing the interaction between 14-3-3beta and p-Bad in SK-N-MC cells. J Pineal Res. 2008;44(1):95-100. doi:10.1111/j.1600-079X.2007.00494.x
Esposito E, Iacono A, Muià C, et al. Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res. 2008;44(1):78-87. doi:10.1111/j.1600-079X.2007.00492.x
Kilic U, Kilic E, Tuzcu Z, et al. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Metab (Lond). 2013;10(1):7. Published 2013 Jan 12. doi:10.1186/1743-7075-10-7
Wang Z, Ma C, Meng CJ, et al. Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J Pineal Res. 2012;53(2):129-137. doi:10.1111/j.1600-079X.2012.00978.x
Aparicio-Soto M, Alarcón-de-la-Lastra C, Cárdeno A, Sánchez-Fidalgo S, Sanchez-Hidalgo M. Melatonin modulates microsomal PGE synthase 1 and NF-E2-related factor-2-regulated antioxidant enzyme expression in LPS-induced murine peritoneal macrophages. Br J Pharmacol. 2014;171(1):134-144. doi:10.1111/bph.12428
Lee YM, Chen HR, Hsiao G, Sheu JR, Wang JJ, Yen MH. Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. J Pineal Res. 2002;33(2):72-80. doi:10.1034/j.1600-079x.2002.01869.x
Audia JP, Yang XM, Crockett ES, et al. Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function. Basic Res Cardiol. 2018;113(5):32. Published 2018 Jul 10. doi:10.1007/s00395-018-0692-z
Lu J, Li J, Hu Y, et al. Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation. Acta Pharm Sin B. 2019;9(4):782-793. doi:10.1016/j.apsb.2018.10.008
Zaoualí MA, Reiter RJ, Padrissa-Altés S, et al. Melatonin protects steatotic and nonsteatotic liver grafts against cold ischemia and reperfusion injury. J Pineal Res. 2011;50(2):213-221. doi:10.1111/j.1600-079X.2010.00831.x
de Oliveira Junior ER, Nascimento TL, Salomão MA, da Silva ACG, Valadares MC, Lima EM. Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone Nanoparticles for the Treatment of Glioblastoma. Pharm Res. 2019;36(9):131. Published 2019 Jul 1. doi:10.1007/s11095-019-2662-z
Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Protective role of melatonin in mitochondrial dysfunction and related disorders. Arch Toxicol. 2015;89(6):923-939. doi:10.1007/s00204-015-1475-z
Ortiz F, García JA, Acuña-Castroviejo D, et al. The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS. J Pineal Res. 2014;56(1):71-81. doi:10.1111/jpi.12099
Mukherjee D, Roy SG, Bandyopadhyay A, Chattopadhyay A, Basu A, Mitra E, Ghosh AK, Reiter RJ, Bandyopadhyay D. Melatonin protects against isoproterenol‐induced myocardial injury in the rat: antioxidative mechanisms. J. Pineal Res. 2010;48: 251-262. DOI: 10.1111/j.1600-079X.2010.00749.x.
Dwaich KH, Al-Amran FG, Al-Sheibani BI, Al-Aubaidy HA. Melatonin effects on myocardial ischemia-reperfusion injury: Impact on the outcome in patients undergoing coronary artery bypass grafting surgery. Int J Cardiol. 2016;221:977-986. doi:10.1016/j.ijcard.2016.07.108
Hardeland R. Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. Int J Mol Sci. 2019;20(5):1223. Published 2019 Mar 11. doi:10.3390/ijms20051223
León J, Escames G, Rodríguez MI, et al. Inhibition of neuronal nitric oxide synthase activity by N1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. J Neurochem. 2006;98(6):2023-2033. doi:10.1111/j.1471-4159.2006.04029.x
Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P. The role of melatonin in acute myocardial infarction. Front Biosci (Landmark Ed). 2012;17(7):2433-2441. Published 2012 Jun 1. doi:10.2741/4063
Bandyopadhyay D, Chattopadhyay A, Ghosh G, Datta AG. Oxidative stress-induced ischemic heart disease: protection by antioxidants. Curr Med Chem. 2004;11(3):369-387. doi:10.2174/0929867043456016
Bandyopadhyay D, Biswas K, Bandyopadhyay U, Reiter RJ, Banerjee RK. Melatonin protects against stress-induced gastric lesions by scavenging the hydroxyl radical. J Pineal Res. 2000;29(3):143-151. doi:10.1034/j.1600-079x.2000.290303.x
Reiter RJ, Tan DX, Acuna-Castroviejo D, Burkhardt S, Karbownik M. Melatonin: Mechanisms and actions as an antioxidant. Curr. Top. Biophys.2000;24: 171–183.
Reiter RJ, Tan DX, Burkhardt S. Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech Ageing Dev. 2002;123(8):1007-1019. doi:10.1016/s0047-6374(01)00384-0
Gitto E, Tan DX, Reiter RJ, et al. Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) in rat liver homogenates. J Pharm Pharmacol. 2001;53(10):1393-1401. doi:10.1211/0022357011777747
Bandyopadhyay D, Bandyopadhyay A, Das PK, Reiter RJ. Melatonin protects against gastric ulceration and increases the efficacy of ranitidine and omeprazole in reducing gastric damage. J Pineal Res. 2002;33(1):1-7. doi:10.1034/j.1600-079x.2002.01107.x
Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol. 2002;54(10):1299-1321. doi:10.1211/002235702760345374
Cheung RT, Tipoe GL, Tam S, Ma ES, Zou LY, Chan PS. Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration. J Pineal Res. 2006;41(4):337-343. doi:10.1111/j.1600-079X.2006.00372.x
Morera AL, Henry M, de La Varga M. Seguridad en el uso de la melatonina [Safety in melatonin use]. Actas Esp Psiquiatr. 2001;29(5):334-337. PMID: 11602091