РОЛЬ АУТОФАГИИ В ИШЕМИЧЕСКОМ И РЕПЕРФУЗИОННОМ ПОВРЕЖДЕНИИ СЕРДЦА
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Ключевые слова

аутофагия
сердце
ишемия
реперфузия

Как цитировать

Воронков, Н. С., & Маслов, Л. Н. (2019). РОЛЬ АУТОФАГИИ В ИШЕМИЧЕСКОМ И РЕПЕРФУЗИОННОМ ПОВРЕЖДЕНИИ СЕРДЦА. Российский физиологический журнал им. И. М. Сеченова, 106(2), 135–156. https://doi.org/10.31857/S0869813920020119

Аннотация

Ишемия/реперфузия (И/Р) сердца приводит к усилению аутофагического потока. Прекондиционирование стимулирует аутофагический поток за счёт активации киназы AMPK и PI3-киназы при ингибировании киназы mTOR. Кардиопротекторный эффект посткондиционирования связан с активацией аутофагии и повышением активности NO-синтазы и AMPK. И/Р стимулирует аутофагию, а гонадэктомия её подавляет. Адаптация к гипоксии оказывает кардиопротекторный эффект, который, возможно, связан с активацией аутофагии. Возможно, что негативный эффект жировой диеты на толерантность сердца к И/Р связан с ингибированием аутофагии. Голодание стимулирует аутофагию, этот эффект сопровождается повышением толерантности сердца к действию И/Р. Окислительный стресс стимулирует аутофагию при И/Р сердца. Супероксидный радикал, генерируемый НАДФН-оксидазой, выступает в роли триггера аутофагии, по-видимому, за счёт активации киназы AMPK. Есть основания полагать, что киназы AMPK, GSK-3β, JNK, MEK и ERK стимулируют аутофагию, а mTOR, Akt- и PI3-киназа ингибируют аутофагию при И/Р сердца. Установлено, что транскрипционные факторы FoxO1, FoxO3, NF-κB и HIF-1α усиливают аутофагию при И/Р сердца. Транскрипционные факторы STAT1 и p53 ингибируют аутофагию в условиях И/Р сердца. miR-325, miR-145 и miR-144 симулируют аутофагию, а miR-30a, miR-221, miR-638 и miR-144 ингибируют аутофагию при И/Р сердца. Представленные данные свидетельствуют, что H2S повышает толерантность сердца к действию И/Р и ингибирует аутофагию. Гемоксигеназа-1 стимулирует аутофагию и предупреждает повреждение митохондрий при гипоксии/реоксигенации кардиомиоцитов. Активация аутофагии во время И/Р может быть протекторной или повреждающей в зависимости от экспериментальной модели. Инфаркт-лимитирующий эффект зависит не только от того, как влияет то или иное соединение на аутофагию, но и от того, как оно влияет на апоптоз, некроптоз и некроз кардиомиоцитов при И/Р сердца.

https://doi.org/10.31857/S0869813920020119
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Литература

De Duve C., Pressman B.C., Gianetto R., Wattiaux R., Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 60(4): 604–617. 1955.

Bainton D.F. The discovery of lysosomes. J Cell Biol. 91(3 Pt 2): 66s–76s. 1981.

De Duve C. Lysosomes revisited. Eur J Biochem. 137(3): 391–397. 1983.

Ashford T.P., Porter K.R. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 12: 198–202. 1962.

Klionsky D.J. Autophagy revisited: A conversation with Christian de Duve. Autophagy. 4(6): 740–743. 2008.

Radewa J. Observations on autophagocytosis phenomena in the blood. Z Rheumaforsch. 22: 36–46. 1963.

Deter R.L., Baudhuin P., De Duve C. Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol. 35(2): C11–С16. 1967.

Deter R.L., De Duve C. Influence of glucagon, an inducer of cellular autophagy, on some physical properties of rat liver lysosomes. J Cell Biol. 33(2): 437–449. 1967.

Sciarretta S., Maejima Y., Zablocki D., Sadoshima J. The role of autophagy in the heart. Annu Rev Physiol. 80: 1–26. 2018.

Shintani T., Klionsky D.J. Autophagy in health and disease: a double-edged sword. Science. 306(5698): 990–995. 2004.

Ravikumar B., Sarkar S., Davies J.E., Futter M., Garcia-Arencibia M., Green-Thompson Z.W., Jimenez-Sanchez M., Korolchuk V.I., Lichtenberg M., Luo S., Massey D.C., Menzies F.M., Moreau K., Narayanan U., in physiology and pathophysiology. Physiol Rev. 90(4): 1383–1435. 2010.

Renna M., Siddiqi F.H., Underwood B.R., Winslow A.R., Rubinsztein D.C. Regulation of mammalian autophagy Singh K.K., Yanagawa B., Quan A., Wang R., Garg A., Khan R., Pan Y., Wheatcroft M.D., Lovren F., Teoh H., Verma S. Autophagy gene fingerprint in human ischemia and reperfusion. J Thorac Cardiovasc Surg. 147(3): 1065–1072. 2014.

Huang C., Andres A.M., Ratliff E.P., Hernandez G., Lee P., Gottlieb R.A. Preconditioning involves selective mitophagy mediated by parkin and p62/SQSTM1. PLoS One. 6(6): e20975. 2011.

Vélez D.E., Hermann R., Barreda Frank M., Mestre Cordero V.E., Savino E.A., Varela A., Marina Prendes M.G. Effects of wortmannin on cardioprotection exerted by ischemic preconditioning in rat hearts subjected to ischemia-reperfusion. J Physiol Biochem. 72(1): 83–91. 2016.

García-Rúa V., Feijóo-Bandín S., Rodríguez-Penas D., Mosquera-Leal A., Abu-Assi E., Beiras A., María Seoane L., Lear P., Parrington J., Portolés M., Roselló-Lletí E., Rivera M., Gualillo O., Parra V., Hill J.A., Rothermel B., González-Juanatey J.R., Lago F. Endolysosomal two-pore channels regulate autophagy in cardiomyocytes. J Physiol. 594(11): 3061–3077. 2016.

Wang B., Zhong S., Zheng F., Zhang Y., Gao F., Chen Y., Lu B., Xu H., Shi G. N-n-butyl haloperidol iodide protects cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy. Oncotarget. 6(28): 24709–24721. 2015.

Hua P., Liu J., Tao J., Zou R., Lin X., Zhang D., Yang S. Efficacy and mechanism of preoperative simvastatin therapy on myocardial protection after extracorporeal circulation. Biomed Res Int. 2017: 6082430. 2017.

Ye G., Fu Q., Jiang L., Li Z. Vascular smooth muscle cells activate PI3K/Akt pathway to attenuate myocardial ischemia/reperfusion-induced apoptosis and autophagy by secreting bFGF. Biomed Pharmacother. 107: 1779–1785. 2018.

Xie H., Xu Q., Jia J., Ao G., Sun Y., Hu L., Alkayed N.J., Wang C., Cheng J. Hydrogen sulfide protects against myocardial ischemia and reperfusion injury by activating AMP-activated protein kinase to restore autophagic flux. Biochem Biophys Res Commun. 458(3): 632–638. 2015.

Shao J., Miao C., Geng Z., Gu M., Wu Y., Li Q. Effect of eNOS on ischemic postconditioning-induced autophagy against ischemia/reperfusion injury in mice. Biomed Res Int. 2019: 5201014. 2019.

Zhao T., Huang X., Han L., Wang X., Cheng H., Zhao Y., Chen Q., Chen J., Cheng H., Xiao R., Zheng M. Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem. 287(28): 23615–23625. 2012.

Kanamori H., Takemura G., Goto K., Maruyama R., Ono K., Nagao K., Tsujimoto A., Ogino A., Takeyama T., Kawaguchi T., Watanabe T., Kawasaki M., Fujiwara T., Fujiwara H., Seishima M., Minatoguchi S. Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion. Am J Physiol. Heart Circ. Physiol. 300(6): H2261–H2271. 2011.

Qian J., Ren X., Wang X., Zhang P., Jones W.K., Molkentin J.D., Fan G.C., Kranias E.G. Blockade of Hsp20 phosphorylation exacerbates cardiac ischemia/reperfusion injury by suppressed autophagy and increased cell death. Circ Res. 105(12): 1223–1231. 2009.

De Meyer G.R., Martinet W. Autophagy in the cardiovascular system. Biochim Biophys Acta. 1793(9): 1485–1495. 2009.

Valentim L., Laurence K.M., Townsend P.A., Carroll C.J., Soond S., Scarabelli T.M., Knight R.A., Latchman D.S., Stephanou A. Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury. J Mol Cell Cardiol. 40(6): 846–852. 2006.

Yan L., Vatner D.E., Kim S.J., Ge H., Masurekar M., Massover W.H., Yang G., Matsui Y., Sadoshima J., Vatner S.F. Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci USA. 102(39): 13807–13812. 2005.

Decker R.S., Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol. 98(2): 425–444. 1980.

Sybers H.D., Ingwall J., DeLuca M. Autophagy in cardiac myocytes. Recent Adv Stud Cardiac Struct Metab. 12: 453–463. 1976.

Sengupta A., Molkentin J.D., Yutzey K.E. FoxO transcription factors promote autophagy in cardiomyocytes. J Biol Chem. 284(41): 28319–28331. 2009.

Yan L., Sadoshima J., Vatner D.E., Vatner S.F. Autophagy in ischemic preconditioning and hibernating myocardium. Autophagy. 5(5): 709–712. 2009.

Sala-Mercado J.A., Wider J., Undyala V.V., Jahania S., Yoo W., Mentzer R.M. Jr., Gottlieb R.A., Przyklenk K. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation. 122(11 Suppl): S179–S184. 2010.

Ma X., Liu H., Foyil S.R., Godar R.J., Weinheimer C.J., Hill J.A., Diwan A. Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation. 125(25): 3170–3181. 2012.

Zhang Y.L., Yao Y.T., Fang N.X., Zhou C.H., Gong J.S., Li L.H. Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats. Acta Pharmacol Sin. 35(6): 758–769. 2014.

Wang Z.G., Wang Y., Huang Y., Lu Q., Zheng L., Hu D., Feng W.K., Liu Y.L., Ji K.T., Zhang H.Y., Fu X.B., Li X.K., Chu M.P., Xiao J. bFGF regulates autophagy and ubiquitinated protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway. Sci Rep. 5: 9287. 2015.

Guo L., Xu J.M., Mo X.Y. Ischemic postconditioning regulates cardiomyocyte autophagic activity following ischemia/reperfusion injury. Mol Med Rep. 12(1): 1169–1176. 2015.

Huang Z., Han Z., Ye B., Dai Z., Shan P., Lu Z., Dai K., Wang C., Huang W. Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes. Eur J Pharmacol. 762: 1–10. 2015.

Ma M.Q., Thapalia B.A., Lin X.H. A 6 hour therapeutic window, optimal for interventions targeting AMPK synergism and apoptosis antagonism, for cardioprotection against myocardial ischemic injury: an experimental study on rats. Am J Cardiovasc Dis. 5(1): 63–71. 2015.

Yu P., Zhang J., Yu S., Luo Z., Hua F., Yuan L., Zhou Z., Liu Q., Du X., Chen S., Zhang L., Xu G. Protective effect of sevoflurane postconditioning against cardiac ischemia/reperfusion injury via ameliorating mitochondrial impairment, oxidative stress and rescuing autophagic clearance. PLoS One. 10(8): e0134666. 2015.

Xu Q., Li X., Lu Y., Shen L., Zhang J., Cao S., Huang X., Bin J., Liao Y. Pharmacological modulation of autophagy to protect cardiomyocytes according to the time windows of ischaemia/reperfusion. Br J Pharmacol. 172(12): 3072–3085. 2015.

Jiang H., Xiao J., Kang B., Zhu X., Xin N., Wang Z. PI3K/SGK1/GSK3β signaling pathway is involved in inhibition of autophagy in neonatal rat cardiomyocytes exposed to hypoxia/reoxygenation by hydrogen sulfide. Exp Cell Res. 345(2): 134–140. 2016.

Yang Y., Li Y., Chen X., Cheng X., Liao Y., Yu X. Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia. J Mol Med. (Berl). 94(6): 711–724. 2016.

Wang J.J., Bie Z.D., Sun C.F. Long noncoding RNA AK088388 regulates autophagy through miR-30a to affect cardiomyocyte injury. J Cell Biochem. 120(6): 10155–10163. 2019.

Gurusamy N., Lekli I., Mukherjee S., Ray D., Ahsan M.K., Gherghiceanu M., Popescu L.M., Das D.K. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res. 86(1): 103–112. 2010.

French C.J., Taatjes D.J., Sobel B.E. Autophagy in myocardium of murine hearts subjected to ischemia followed by reperfusion. Histochem Cell Biol. 134(5): 519–526. 2010.

Cao X., Wang X., Ling Y., Song X., Yang P., Liu Y., Liu L., Wang L., Guo J., Chen A. Comparison of the degree of autophagy in neonatal rat cardiomyocytes and H9c2 cells exposed to hypoxia/reoxygenation. Clin Lab. 60(5): 809–814. 2014.

Hu S., Cao S., Tong Z., Liu J. FGF21 protects myocardial ischemia-reperfusion injury through reduction of miR-145-mediated autophagy. Am J Transl Res. 10(11): 3677–3688. 2018.

Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res. 116(4): 674–699. 2015.

Gurusamy N., Lekli I., Gorbunov N.V., Gherghiceanu M., Popescu L.M., Das D.K. Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein. J Cell Mol Med. 13(2): 373–387. 2009.

Gedik N., Thielmann M., Kottenberg E., Peters J., Jakob H., Heusch G., Kleinbongard P. No evidence for activated autophagy in left ventricular myocardium at early reperfusion with protection by remote ischemic preconditioning in patients undergoing coronary artery bypass grafting. PLoS One. 9(5): e96567. 2014.

Rohailla S., Clarizia N., Sourour M., Sourour W., Gelber N., Wei C., Li J., Redington A.N. Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling. PLoS One. 9(10): e111291. 2014.

Dosenko V.E., Nagibin V.S., Tumanovskaya L.V., Zagoriy V.Y., Moibenko A.A., Vaage J. Proteasome inhibitors eliminate protective effect of postconditioning in cultured neonatal cardiomyocytes. Fiziol Zh. 52(3): 15–24. 2006.

Wagner C., Tillack D., Simonis G., Strasser R.H., Weinbrenner C. Ischemic post-conditioning reduces infarct size of the in vivo rat heart: role of PI3-K, mTOR, GSK-3beta, and apoptosis. Mol Cell Biochem. 339(1-2): 135–147. 2010.

Wei C., Li H., Han L., Zhang L., Yang X. Activation of autophagy in ischemic postconditioning contributes to cardioprotective effects against ischemia/reperfusion injury in rat hearts. J Cardiovasc Pharmacol. 61(5): 416–422. 2013.

Chen C., Hu L.X., Dong T., Wang G.Q., Wang L.H., Zhou X.P., Jiang Y., Murao K., Lu S.Q., Chen J.W., Zhang G.X. Apoptosis and autophagy contribute to gender difference in cardiac ischemia-reperfusion induced injury in rats. Life Sci. 93(7): 265–270. 2013.

Le T.Y., Ashton A.W., Mardini M., Stanton P.G., Funder J.W., Handelsman D.J., Mihailidou A.S. Role of androgens in sex differences in cardiac damage during myocardial infarction. Endocrinology. 155(2): 568–575. 2014.

Hu Y., Sun Q., Li Z., Chen J., Shen C., Song Y., Zhong Q. High basal level of autophagy in high-altitude residents attenuates myocardial ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 148(4): 1674–1680. 2014.

Sciarretta S., Zhai P., Shao D., Maejima Y., Robbins J., Volpe M., Condorelli G., Sadoshima J. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation. 125(9): 1134–1146. 2012.

Godar R.J., Ma X., Liu H., Murphy J.T., Weinheimer C.J., Kovacs A., Crosby S.D., Saftig P., Diwan A. Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. Autophagy. 11(9): 1537–1560. 2015.

Hariharan N., Zhai P., Sadoshima J. Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal. 14(11): 2179–2190. 2011.

Sengupta A., Molkentin J.D., Paik J.H., DePinho R.A., Yutzey K.E. FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress. J Biol Chem. 286(9): 7468–7478. 2011.

Liu L., Jin X., Hu C.F., Li R., Zhou Z., Shen C.X. Exosomes derived from mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways. Cell Physiol Biochem. 43(1): 52–68. 2017.

Sciarretta S., Zhai P., Shao D., Zablocki D., Nagarajan N., Terada L.S., Volpe M., Sadoshima J. Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 pathway. Circ Res. 113(11): 1253–1264. 2013.

Krylatov A.V., Maslov L.N., Voronkov N.S., Boshchenko A.A., Popov S.V., Gomez L., Wang H., Jaggi A.S., Downey J.M. Reactive oxygen species as intracellular signaling molecules in the cardiovascular system. Curr Cardiol Rev. 14(4): 290–300. 2018.

Shiomi M., Miyamae M., Takemura G., Kaneda K., Inamura Y., Onishi A., Koshinuma S., Momota Y., Minami T., Figueredo V.M. Sevoflurane induces cardioprotection through reactive oxygen species-mediated upregulation of autophagy in isolated guinea pig hearts. J Anesth. 28(4): 593–600. 2014.

Matsui Y., Takagi H., Qu X., Abdellatif M., Sakoda H., Asano T., Levine B., Sadoshima J. 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(6): 914–922. 2007.

Aoyagi T., Kusakari Y., Xiao C.Y., Inouye B.T., Takahashi M., Scherrer-Crosbie M., Rosenzweig A., Hara K., Matsui T. Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol. Heart Circ Physiol. 303(1): H75–H85. 2012.

Zhao M., Sun L., Yu X.J., Miao Y., Liu J.J., Wang H., Ren J., Zang W.J. Acetylcholine mediates AMPK-dependent autophagic cytoprotection in H9c2 cells during hypoxia/reoxygenation injury. Cell Physiol Biochem. 32(3): 601–613. 2013.

Sciarretta S., Volpe M., Sadoshima J. Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res. 114(3): 549–564. 2014.

Xu J., Qin X., Cai X., Yang L., Xing Y., Li J., Zhang L., Tang Y., Liu J., Zhang X., Gao F. Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion. Biochim Biophys Acta. 1852(2): 262–270. 2015.

Huang L., Dai K., Chen M., Zhou W., Wang X., Chen J., Zhou W. The AMPK agonist PT1 and mTOR inhibitor 3HOI-BA-01 protect cardiomyocytes after ischemia through induction of autophagy. J Cardiovasc Pharmacol Ther. 21(1): 70–81. 2016.

Wang A., Zhang H., Liang Z., Xu K., Qiu W., Tian Y., Guo H., Jia J., Xing E., Chen R., Xiang Z., Liu J. U0126 attenuates ischemia/reperfusion-induced apoptosis and autophagy in myocardium through MEK/ERK/EGR-1 pathway. Eur J Pharmacol. 788: 280–285. 2016.

McCormick J., Suleman N., Scarabelli T.M., Knight R.A., Latchman D.S., Stephanou A. STAT1 deficiency in the heart protects against myocardial infarction by enhancing autophagy. J Cell Mol Med. 16(2): 386–393. 2012.

Hoshino A., Matoba S., Iwai-Kanai E., Nakamura H., Kimata M., Nakaoka M., Katamura M., Okawa Y., Ariyoshi M., Mita Y., Ikeda K., Ueyama T., Okigaki M., Matsubara H. p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia. J Mol Cell Cardiol. 52(1): 175–184. 2012.

Zeng M., Wei X., Wu Z., Li W., Li B., Zhen Y., Chen J., Wang P., Fei Y. NF-κB-mediated induction of autophagy in cardiac ischemia/reperfusion injury. Biochem Biophys Res Commun. 436(2): 180–185. 2013.

Haar L., Ren X., Liu Y., Koch S.E., Goines J., Tranter M., Engevik M.A., Nieman M., Rubinstein J., Jones W.K. Acute consumption of a high-fat diet prior to ischemia-reperfusion results in cardioprotection through NF-κB-dependent regulation of autophagic pathways. Am J Physiol. Heart Circ Physiol. 307(12): H1705–Р1713. 2014.

Gui L., Liu B., Lv G. Hypoxia induces autophagy in cardiomyocytes via a hypoxia-inducible factor 1-dependent mechanism. Exp Ther Med. 11(6): 2233–2239. 2016.

Fromm B., Billipp T., Peck L.E., Johansen M., Tarver J.E., King B.L., Newcomb J.M., Sempere L.F., Flatmark K., Hovig E., Peterson K.J. A uniform system for the annotation of vertebrate microRNA genes and the evolution of the human microRNAome. Annu Rev Genet. 49: 213–242. 2015.

Xiao J., Zhu X., He B., Zhang Y., Kang B., Wang Z., Ni X. MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J Biomed Sci. 18: 35. 2011.

Bo L., Su-Ling D., Fang L., Lu-Yu Z., Tao A., Stefan D., Kun W., Pei-Feng L. Autophagic program is regulated by miR-325. Cell Death Differ. 21(6): 967–977. 2014.

Li J., Rohailla S., Gelber N., Rutka J., Sabah N., Gladstone R.A., Wei C., Hu P., Kharbanda R.K., Redington A.N. MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res Cardiol. 109(5): 423. 2014.

Li X., Zeng Z., Li Q., Xu Q., Xie J., Hao H., Luo G., Liao W., Bin J., Huang X., Liao Y. Inhibition of microRNA-497 ameliorates anoxia/reoxygenation injury in cardiomyocytes by suppressing cell apoptosis and enhancing autophagy. Oncotarget. 6(22): 18829–18844. 2015.

Chen Q., Zhou Y., Richards A.M., Wang P. Up-regulation of miRNA-221 inhibits hypoxia/reoxygenation-induced autophagy through the DDIT4/mTORC1 and Tp53inp1/p62 pathways. Biochem Biophys Res Commun. 474(1): 168–174. 2016.

Zhao P., Zhang B.L., Liu K., Qin B., Li Z.H. Overexpression of miR-638 attenuated the effects of hypoxia/reoxygenation treatment on cell viability, cell apoptosis and autophagy by targeting ATG5 in the human cardiomyocytes. Eur Rev Med Pharmacol Sci. 22(23): 8462–8471. 2018.

Xiao J., Zhu X., Kang B., Xu J., Wu L., Hong J., Zhang Y., Ni X., Wang Z. Hydrogen sulfide attenuates myocardial hypoxia-reoxygenation injury by inhibiting autophagy via mTOR activation. Cell Physiol Biochem. 37(6): 2444–2453. 2015.

Chen J., Gao J., Sun W., Li L., Wang Y., Bai S., Li X., Wang R., Wu L., Li H., Xu C. Involvement of exogenous H2S in recovery of cardioprotection from ischemic post-conditioning via increase of autophagy in the aged hearts. Int J Cardiol. 220: 681–692. 2016.

Chen D., Jin Z., Zhang J., Jiang L., Chen K., He X., Song Y., Ke J., Wang Y. HO-1 protects against hypoxia/reoxygenation-induced mitochondrial dysfunction in H9c2 cardiomyocytes. PLoS One. 11(5): e0153587. 2016.

Przyklenk K., Undyala V.V., Wider J., Sala-Mercado J.A., Gottlieb R.A., Mentzer R.M Jr. Acute induction of autophagy as a novel strategy for cardioprotection: getting to the heart of the matter. Autophagy. 7(4): 432–433. 2011.

Loos B., Genade S., Ellis B., Lochner A., Engelbrecht A.M. At the core of survival: autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury. Exp Cell Res. 317(10): 1437–1453. 2011.

Chen H.H., Mekkaoui C., Cho H., Ngoy S., Marinelli B., Waterman P., Nahrendorf M., Liao R., Josephson L., Sosnovik D.E. Fluorescence tomography of rapamycin-induced autophagy and cardioprotection in vivo. Circ Cardiovasc Imaging. 6(3): 441–447. 2013.

Yang S.S., Liu Y.B., Yu J.B., Fan Y., Tang S.Y., Duan W.T., Wang Z., Gan R.T., Yu B. Rapamycin protects heart from ischemia/reperfusion injury independent of autophagy by activating PI3 kinase-Akt pathway and mitochondria KATP channel. Pharmazie. 65(10): 760–765. 2010.

Yang K., Xu C., Li X., Jiang H. Combination of D942 with curcumin protects cardiomyocytes from ischemic damage through promoting autophagy. J Cardiovasc Pharmacol Ther. 18(6): 570–581. 2013.

Wu X., He L., Cai Y., Zhang G., He Y., Zhang Z., He X., He Y., Zhang G., Luo J. Induction of autophagy contributes to the myocardial protection of valsartan against ischemia‑reperfusion injury. Mol Med Rep. 8(6): 1824–1830. 2013.

Andres A.M., Hernandez G., Lee P., Huang C., Ratliff E.P., Sin J., Thornton C.A., Damasco M.V., Gottlieb R.A. Mitophagy is required for acute cardioprotection by simvastatin. Antioxid Redox Signal. 21(14): 1960–1973. 2014.

Xie M., Kong Y., Tan W., May H., Battiprolu P.K., Pedrozo Z., Wang Z.V., Morales C., Luo X., Cho G., Jiang N., Jessen M.E., Warner J.J., Lavandero S., Gillette T.G., Turer A.T., Hill J.A. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 129(10): 1139–1151. 2014.

Hermann R., Vélez D.E., Rusiecki T.M., Fernández Pazos Mde L., Mestre Cordero V.E., Marina Prendes M.G., Perazzo Rossini J.C., Savino E.A., Varela A. Effects of 3-methyladenine on isolated left atria subjected to simulated ischaemia-reperfusion. Clin Exp Pharmacol Physiol. 42(1): 41–51. 2015.

Wu X., He L., Chen F., He X., Cai Y., Zhang G., Yi Q., He M., Luo J. Impaired autophagy contributes to adverse cardiac remodeling in acute myocardial infarction. PLoS One. 9(11): e112891. 2014.

Zhang J., Nadtochiy S.M., Urciuoli W.R., Brookes P.S. The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy. Am J Physiol. Heart Circ Physiol. 310(1): H29–H38. 2016.

Liu L., Wu Y., Huang X. Orientin protects myocardial cells against hypoxia-reoxygenation injury through induction of autophagy. Eur J Pharmacol. 776: 90–98. 2016.

Ma Y., Gai Y., Yan J., Li J., Zhang Y. Puerarin attenuates anoxia/reoxygenation injury through enhancing Bcl-2 associated athanogene 3 expression, a modulator of apoptosis and autophagy. Med Sci Monit. 22: 977–983. 2016.

Wang Y., Yang Z., Zheng G., Yu L., Yin Y., Mu N., Ma H. Metformin promotes autophagy in ischemia/reperfusion myocardium via cytoplasmic AMPKα1 and nuclear AMPKα2 pathways. Life Sci. 225: 64–71. 2019.

Zhao R., Xie E., Yang X., Gong B. Alliin alleviates myocardial ischemia-reperfusion injury by promoting autophagy. Biochem Biophys Res Commun. 512(2): 236–243. 2019.

Ren Z., Xiao W., Zeng Y., Liu M.H., Li G.H., Tang Z.H., Qu S.L., Hao Y.M., Yuan H.Q., Jiang Z.S. Fibroblast growth factor-21 alleviates hypoxia/reoxygenation injury in H9c2 cardiomyocytes by promoting autophagic flux. Int J Mol Med. 43(3): 1321–1330. 2019.

Qiao S.G., Sun Y., Sun B., Wang A., Qiu J., Hong L., An J.Z., Wang C., Zhang H.L. Sevoflurane postconditioning protects against myocardial ischemia/reperfusion injury by restoring autophagic flux via an NO-dependent mechanism. Acta Pharmacol Sin. 40(1): 35–45. 2019.

Meyer G., Czompa A., Reboul C., Csepanyi E., Czegledi A., Bak I., Balla G., Balla J., Tosaki A., Lekli I. The cellular autophagy markers Beclin-1 and LC3B-II are increased during reperfusion in fibrillated mouse hearts. Curr Pharm Des. 19(39): 6912–6918. 2013.

Cao X., Chen A., Yang P., Song X., Liu Y., Li Z., Wang X., Wang L., Li Y. Alpha-lipoic acid protects cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy. Biochem Biophys Res Commun. 441(4): 935–940. 2013.

Bouhidel J.O., Wang P., Siu K.L., Li H., Youn J.Y., Cai H. Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy. Biochim Biophys Acta. 1852(2): 277–289. 2015.

Xiao J., Zhu X., Ji G., Yang Q., Kang B., Zhao J., Yao F., Wu L., Ni X., Wang Z. Ulinastatin protects cardiomyocytes against ischemia‑reperfusion injury by regulating autophagy through mTOR activation. Mol Med Rep. 10(4): 1949–1953. 2014.

Yao T., Ying X., Zhao Y., Yuan A., He Q., Tong H., Ding S., Liu J., Peng X., Gao E., Pu J., He B. Vitamin D receptor activation protects against myocardial reperfusion injury through inhibition of apoptosis and modulation of autophagy. Antioxid Redox Signal. 22(8): 633–650. 2015.

Xie H., Liu Q., Qiao S., Jiang X., Wang C. Delayed cardioprotection by sevoflurane preconditioning: a novel mechanism via inhibiting Beclin 1-mediated autophagic cell death in cardiac myocytes exposed to hypoxia/reoxygenation injury. Int J Clin Exp Pathol. 8(1): 217–226. 2015b.

Cao J., Xie H., Sun Y., Zhu J., Ying M., Qiao S., Shao Q., Wu H., Wang C. Sevoflurane post-conditioning reduces rat myocardial ischemia reperfusion injury through an increase in NOS and a decrease in phopshorylated NHE1 levels. Int J Mol Med. 36(6): 1529–1337. 2015.

Zhou L.Y., Zhai M., Huang Y., Xu S., An T., Wang Y.H., Zhang R.C., Liu C.Y., Dong Y.H., Wang M., Qian L.L., Ponnusamy M., Zhang Y.H., Zhang J., Wang K. The circular RNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway. Cell Death Differ. 26(7): 1299–1315. 2019.