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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

The Newly Proposed Mechanism of Cardiomyocyte Protection of Carvedilol-Anti-Apoptosis Pattern of Carvedilol in Anoxia by Inducing AutophagyPartly through the AMPK/mTOR Pathway

Author(s):Jingru Li,Chaozhong Li,Guihu Sun,Longjun Li,Yongli Zeng,Huawei Wang,Xinyu Wu,Ping Yang,Yunzhu Peng* andLuqiao Wang*

Volume 20, Issue 10, 2023

Published on: 18 August, 2022

Page: [1600 - 1609]Pages: 10

DOI:10.2174/1570180819666220513150100

Price: $65

Abstract

Purpose: To investigate the underlying mechanism of cardiomyocyte protection of carvedilolbased on autophagy and apoptosis.

Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to various concentrations of carvedilolbefore anoxia, and pretreated with 3-MA or compound C for inhibiting autophagy or p-AMPK expression.CCK-8 colorimeter and flow cytometry were used to determine the cell viability and apoptoticrates. The variation of mRNA and protein was measured by RT-PCR and Western blot. The presence ofautophagosomes was observed by electron microscopy.

Results: First, we found that carvedilol increased autophagic marker levels in a concentration-dependentmanner and the number of autophagosomes in NRVMs. Moreover, carvedilol substantially enhanced theviability and noticeably reduced the CK, MDA and LDH levels and cell apoptosis rate compared with theanoxia group. In addition, carvedilol decreased the levels of caspase-3 and Bim in mRNA and protein, butsuch effect was blocked by the special autophagy inhibitor-3-MA, and the number of autophagosomeswas significantly decreased when treated with 3-MA, indicating that carvedilol exhibited anti-apoptoticand anti-injury effects by inducing autophagy in anoxia NRVMs, but these effects can be abolished byadding 3-MA to suppress autophagy. Finally, the carvedilol treatment-induced autophagy by enhancingthe activation of p-AMPK and inhibiting p-mTOR. Electron microscopy presented that the number ofautophagosomes was significantly decreased when treating with compound C, indicating that carvedilolinduced autophagy in anoxia NRVMs partly by the AMPK-mTOR signaling pathway.

Conclusion: Carvedilol has cardioprotection by inducing autophagy against apoptosis partly through theAMPK/mTOR pathway during anoxia in NRVMs.

Keywords:Carvedilol, autophagy, anoxia, apoptosis, AMPK/mTOR signal pathway, cardiomyocyte protection.

Graphical Abstract

[1]
Fortuni, F.; Ferlini, M.; Leonardi, S. Parenteral antithrombotic therapy during primary percutaneous coronary intervention.Minerva Cardioangiol.,2018,66(4), 411-421.
[http://dx.doi.org/10.23736/S0026-4725.18.04619-4] [PMID: 29393605]
[2]
Tibaut, M.; Mekis, D.; Petrovic, D. Pathophysiology of myocardial infarction and acute management strategies.Cardiovasc Hematol Agents Med Chem,,2017,14(3), 150-159.
[http://dx.doi.org/10.2174/1871525714666161216100553]
[3]
Du, J.; Liu, Y.; Fu, J. Autophagy and heart failure.Adv. Exp. Med. Biol.,2020,1207, 223-227.
[http://dx.doi.org/10.1007/978-981-15-4272-5_16] [PMID: 32671751]
[4]
Shirakabe, A.; Ikeda, Y.; Sciarretta, S.; Zablocki, D.K.; Sadoshima, J. Aging and autophagy in the heart.Circ. Res.,2016,118(10), 1563-1576.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.307474] [PMID: 27174950]
[5]
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.,2019,225, 64-71.
[http://dx.doi.org/10.1016/j.lfs.2019.04.002] [PMID: 30953640]
[6]
Ahn, J.; Kim, J. Nutritional status and cardiac autophagy.Diabetes Metab. J.,2013,37(1), 30-35.
[http://dx.doi.org/10.4093/dmj.2013.37.1.30] [PMID: 23441078]
[7]
Wang, L.Q.; Cheng, X.S.; Huang, C.H.; Huang, B.; Liang, Q. Rapamycin protects cardiomyocytes against anoxia/reoxygenation injury by inducing autophagy through the PI3k/Akt pathway.J. Huazhong Univ. Sci,2015,35(1), 10-15.
[http://dx.doi.org/10.1007/s11596-015-1381-x]
[8]
Ortiz, V.D.; Türck, P.; Teixeira, R.; Lima-Seolin, B.G.; Lacerda, D.; Fraga, S.F.; Hickmann, A.; Gatelli Fernandes, T.R.; Ortiz, V.D.; Türck, P.; Teixeira, R.; Lima-Seolin, B.G.; Lacerda, D.; Fraga, S.F.; Hickmann, A.; Gatelli Fernandes, T.R.; Belló-Klein, A.; Luz de Castro, A.; da Rosa Araujo, A.S. Carvedilol and thyroid hormones co-administration mitigates oxidative stress and improves cardiac function after acute myocardial infarction.Eur. J. Pharmacol.,2019,854, 159-166.
[http://dx.doi.org/10.1016/j.ejphar.2019.04.024] [PMID: 30991047]
[9]
Feuerstein, G.Z.; Ruffolo, R.R. Jr Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection.Eur. Heart J.,1996,35(1), 10-15.
[http://dx.doi.org/10.1093/eurheartj/17.suppl_B.24]
[10]
Ferreira, J.P.; Girerd, N.; Gregson, J.; Latar, I.; Sharma, A.; Pfeffer, M.A.; McMurray, J.J.V.; Abdul-Rahim, A.H.; Pitt, B.; Dickstein, K.; Rossignol, P.; Zannad, F. High-risk myocardial infarction database initiative. Stroke risk in patients with reduced ejection fraction after myocardial infarction without atrial fibrillation.J. Am. Coll. Cardiol.,2018,71(7), 727-735.
[http://dx.doi.org/10.1016/j.jacc.2017.12.011] [PMID: 29447733]
[11]
Dargie, H.J. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial.Lancet,2001,357(9266), 1385-1390.
[http://dx.doi.org/10.1016/S0140-6736(00)04560-8] [PMID: 11356434]
[12]
Dargie, H.J. Design and methodology of the CAPRICORN trial - a randomised double blind placebo controlled study of the impact of carvedilol on morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction.Eur. J. Heart Fail.,2000,2(3), 325-332.
[http://dx.doi.org/10.1016/S1388-9842(00)00098-2] [PMID: 10938495]
[13]
Carreira, R.S.; Monteiro, P.; Gon Alves, L.M.; Providência, L.A. Carvedilol: Just another Beta-blocker or a powerful cardioprotector?Cardiovasc. Hematol. Disord. Drug Targets,2006,6(4), 257-266.
[http://dx.doi.org/10.2174/187152906779010746] [PMID: 17378771]
[14]
Machado, V.; Cabral, A.; Monteiro, P.; Gonçalves, L.; Providência, L. A. Carvedilol as a protector against the cardiotoxicity induced by anthracyclines (doxorubicin).Portuguese journal of cardiology An official journal of the Portuguese Society of Cardiology,2008,27(10), 1277-1296.
[15]
Ruffolo, R.R., Jr; Boyle, D.A.; Venuti, R.P.; Lukas, M.A. Preclinical and clinical pharmacology of carvedilol.J. Hum. Hypertens.,1993,7(Suppl. 1), S2-S15.
[PMID: 8487245]
[16]
Bayoumi, A.S.; Park, K.M.; Wang, Y.; Teoh, J.P.; Aonuma, T.; Tang, Y.; Su, H.; Weintraub, N.L.; Kim, I.M. A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes.J. Mol. Cell. Cardiol.,2018,114, 72-82.
[http://dx.doi.org/10.1016/j.yjmcc.2017.11.003] [PMID: 29122578]
[17]
Shirazi-Tehrani, E.; Firouzabadi, N.; Tamaddon, G.; Bahramali, E.; Vafadar, A. Carvedilol alters circulating MiR-1 and MiR-214 in heart failure.Pharm. Genomics Pers. Med.,2020,13, 375-383.
[http://dx.doi.org/10.2147/PGPM.S263740] [PMID: 32943906]
[18]
Ortiz, V.D.; Türck, P.; Teixeira, R.; Belló-Klein, A.; de Castro, A.L.; Araujo, A.S.D.R. Effects of carvedilol and thyroid hormones co-administration on apoptotic and survival proteins in the heart after acute myocardial infarction.J. Cardiovasc. Pharmacol.,2020,76(6), 698-707.
[http://dx.doi.org/10.1097/FJC.0000000000000923] [PMID: 33105324]
[19]
Meng, D.; Li, Z.; Wang, G.; Ling, L.; Wu, Y.; Zhang, C. Carvedilol attenuates liver fibrosis by suppressing autophagy and promoting apoptosis in hepatic stellate cells.Biomed. Pharmacother.,2018,108, 1617-1627.
[http://dx.doi.org/10.1016/j.biopha.2018.10.005]
[20]
Zhang, J.L.; Lu, J.K.; Chen, D.; Cai, Q.; Li, T.X.; Wu, L.S.; Wu, X.S. Myocardial autophagy variation during acute myocardial infarction in rats: The effects of carvedilol.Chin. Med. J. (Engl.),2009,122(19), 2372-2379.
[PMID: 20079142]
[21]
Sun, Z.; Wang, L.; Han, L.; Wang, Y.; Zhou, Y.; Li, Q.; Wu, Y.; Talabieke, S.; Hou, Y.; Wu, L.; Liu, R.; Fu, Z.; You, H.; Li, B.Y.; Zheng, Y.; Luo, D. Functional calsequestrin-1 is expressed in the heart and its deficiency is causally related to malignant hyperthermia-like arrhythmia.Circulation,2021,144(10), 788-804.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053255] [PMID: 34162222]
[22]
Li, C.; Liu, Y.; Liu, H. Expression of c-Myc and Beclin-1 in skin of rats after burn.Exp. Ther. Med.,2018,16(4), 2917-2921.
[http://dx.doi.org/10.3892/etm.2018.6582] [PMID: 30233665]
[23]
Wong, W.T.; Li, L.H.; Rao, Y.K.; Yang, S.P.; Cheng, S.M.; Lin, W.Y.; Cheng, C.C.; Chen, A.; Hua, K.F. Repositioning of the β-blocker carvedilol as a novel autophagy inducer that inhibits the NLRP3 inflammasome.Front. Immunol.,2018,9, 1920.
[http://dx.doi.org/10.3389/fimmu.2018.01920] [PMID: 30186288]
[24]
Zhu, M.; Pan, J.; Zhang, M.; Tong, X.; Zhang, Y.; Zhang, Z.; Liang, Z.; Zhang, X.; Hu, X.; Xue, R.; Cao, G.; Gong, C. Bombyx mori cypovirus (BmCPV) induces PINK1-Parkin mediated mitophagy via interaction of VP4 with host Tom40.Dev. Comp. Immunol.,2022,126, 104244.
[http://dx.doi.org/10.1016/j.dci.2021.104244] [PMID: 34450127]
[25]
Ho, W.M.; Akyol, O.; Reis, H.; Reis, C.; McBride, D.; Thome, C.; Zhang, J. Autophagy after subarachnoid hemorrhage: Can cell death be good?Curr. Neuropharmacol.,2018,16(9), 1314-1319.
[http://dx.doi.org/10.2174/1570159X15666171123200646] [PMID: 29173174]
[26]
Dasgupta, B.; Seibel, W. Compound C/Dorsomorphin: Its use and misuse as an AMPK inhibitor.Methods Mol. Biol.,2018,1732, 195-202.
[http://dx.doi.org/10.1007/978-1-4939-7598-3_12] [PMID: 29480476]
[27]
Sahu, B.D.; Koneru, M.; Bijargi, S.R.; Kota, A.; Sistla, R. Chromium-induced nephrotoxicity and ameliorative effect of carvedilol in rats: Involvement of oxidative stress, apoptosis and inflammation.Chem. Biol. Interact.,2014,223, 69-79.
[http://dx.doi.org/10.1016/j.cbi.2014.09.009] [PMID: 25245570]
[28]
Misrielal, C.; Mauthe, M.; Reggiori, F.; Eggen, B.J.L. Autophagy in multiple sclerosis: Two sides of the same coin.Front. Cell. Neurosci.,2020,14, 603710.
[http://dx.doi.org/10.3389/fncel.2020.603710] [PMID: 33328897]
[29]
Sridhar, S.; Botbol, Y.; Macian, F.; Cuervo, A.M. Autophagy and disease: Always two sides to a problem.J. Pathol.,2012,226(2), 255-273.
[http://dx.doi.org/10.1002/path.3025] [PMID: 21990109]
[30]
Hu, H.; Li, X.; Ren, D.; Tan, Y.; Chen, J.; Yang, L.; Chen, R.; Li, J.; Zhu, P. The cardioprotective effects of carvedilol on ischemia and reperfusion injury by AMPK signaling pathway.Biomed. Pharmacother.,2019,117, 109106.
[http://dx.doi.org/10.1016/j.biopha.2019.109106]
[31]
Tamargo-Gómez, I.; Mariño, G. AMPK: Regulation of metabolic dynamics in the context of autophagy.Int. J. Mol. Sci.,2018,19(12), E3812.
[http://dx.doi.org/10.3390/ijms19123812] [PMID: 30501132]
[32]
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.,2016,21(1), 70-81.
[http://dx.doi.org/10.1177/1074248415581177] [PMID: 25868658]

Letters in Drug Design & Discovery

Title:The Newly Proposed Mechanism of Cardiomyocyte Protection of Carvedilol-Anti-Apoptosis Pattern of Carvedilol in Anoxia by Inducing AutophagyPartly through the AMPK/mTOR Pathway

Volume: 20Issue: 10

Author(s):Jingru Li, Chaozhong Li, Guihu Sun, Longjun Li, Yongli Zeng, Huawei Wang, Xinyu Wu, Ping Yang, Yunzhu Peng*Luqiao Wang*

Affiliation:

                  • Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
                  • Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

                  Keywords:Carvedilol, autophagy, anoxia, apoptosis, AMPK/mTOR signal pathway, cardiomyocyte protection.

                  Abstract:

                  Purpose: To investigate the underlying mechanism of cardiomyocyte protection of carvedilolbased on autophagy and apoptosis.

                  Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to various concentrations of carvedilolbefore anoxia, and pretreated with 3-MA or compound C for inhibiting autophagy or p-AMPK expression.CCK-8 colorimeter and flow cytometry were used to determine the cell viability and apoptoticrates. The variation of mRNA and protein was measured by RT-PCR and Western blot. The presence ofautophagosomes was observed by electron microscopy.

                  Results: First, we found that carvedilol increased autophagic marker levels in a concentration-dependentmanner and the number of autophagosomes in NRVMs. Moreover, carvedilol substantially enhanced theviability and noticeably reduced the CK, MDA and LDH levels and cell apoptosis rate compared with theanoxia group. In addition, carvedilol decreased the levels of caspase-3 and Bim in mRNA and protein, butsuch effect was blocked by the special autophagy inhibitor-3-MA, and the number of autophagosomeswas significantly decreased when treated with 3-MA, indicating that carvedilol exhibited anti-apoptoticand anti-injury effects by inducing autophagy in anoxia NRVMs, but these effects can be abolished byadding 3-MA to suppress autophagy. Finally, the carvedilol treatment-induced autophagy by enhancingthe activation of p-AMPK and inhibiting p-mTOR. Electron microscopy presented that the number ofautophagosomes was significantly decreased when treating with compound C, indicating that carvedilolinduced autophagy in anoxia NRVMs partly by the AMPK-mTOR signaling pathway.

                  Conclusion: Carvedilol has cardioprotection by inducing autophagy against apoptosis partly through theAMPK/mTOR pathway during anoxia in NRVMs.

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                  Cite this article as:

                  Li Jingru, Li Chaozhong, Sun Guihu, Li Longjun, Zeng Yongli, Wang Huawei, Wu Xinyu, Yang Ping, Peng Yunzhu*, Wang Luqiao*, The Newly Proposed Mechanism of Cardiomyocyte Protection of Carvedilol-Anti-Apoptosis Pattern of Carvedilol in Anoxia by Inducing AutophagyPartly through the AMPK/mTOR Pathway, Letters in Drug Design & Discovery 2023; 20 (10) .https://dx.doi.org/10.2174/1570180819666220513150100

                  DOI
                  https://dx.doi.org/10.2174/1570180819666220513150100                  		Print ISSN
                  1570-1808
                  Publisher Name
                  Bentham Science Publisher                  		Online ISSN
                  1875-628X
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