miR-153 regulates apoptosis and autophagy of cardiomyocytes by targeting Mcl-1

Zou,Yuhai; Liu,Wenting; Zhang,Jinxia; Xiang,Dingcheng

doi:10.3892/mmr.2016.5309

miR-153 regulates apoptosis and autophagy of cardiomyocytes by targeting Mcl-1

Authors:
- Yuhai Zou
- Wenting Liu
- Jinxia Zhang
- Dingcheng Xiang
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Affiliations: Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of ENT, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, P.R. China, Department of Cardiology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China
Published online on: May 19, 2016 https://doi.org/10.3892/mmr.2016.5309
Pages: 1033-1039

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Abstract

MicroRNAs (miRs) are a class of important regulators, which are involved in the regulation of apoptosis. Oxidative stress‑induced apoptosis is the predominant factor accounting for cardiac ischemia‑reperfusion injury. miR‑153 has been previously shown to have an antitumor effect in cancer. However, whether miR‑153 is involved in oxidative stress‑induced apoptosis in the heart remains to be elucidated. To this end, the present study used reverse transcription‑quantitative polymerase chain reaction to detect miR-153 levels upon oxidative stress, and evaluated apoptosis, autophagy and expression of critical genes by western blotting. A luciferase assay was also used to confirm the potential target gene. In the present study, it was found that the expression of miR‑153 was significantly increased upon H2O2 stimulation, and the inhibition of endogenous miR‑153 decreased apoptosis. To further identify the mechanism underlying the pro‑apoptotic effect of miR‑153, the present study analyzed the 3'untranslated region of myeloid cell leukemia‑1 (Mcl‑1), and found that Mcl‑1 was potentially targeted by miR‑153. The forced expression of miR‑153 inhibited the expression of Mcl‑1 and luciferase activity, which was reversed by its antisense inhibitor. Furthermore, it was shown that the inhibition of miR‑153 induced autophagy during oxidative stress, and that its effects of autophagy induction and apoptosis inhibition were efficiently abrogated by Mcl‑1 small interfering RNA. In conclusion, the results of the present study elucidated a novel mechanism by which miR‑153 regulates the survival of cardimyocytes during oxidative stress through the modulation of apoptosis and autophagy. These effects may be mediated directly by targeting Mcl‑1. These finding revealed the potential clinical value of miR‑153 in the treatment of cardiovascular disease.

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1	Hafstad AD, Nabeebaccus AA and Shah AM: Novel aspects of ROS signalling in heart failure. Basic Res Cardiol. 108:3592013. View Article : Google Scholar : PubMed/NCBI
2	Wang J and Martin JF: Macro advances in microRNAs and myocardial regeneration. Curr Opin Cardiol. 29:207–213. 2014. View Article : Google Scholar : PubMed/NCBI
3	Sala V, Bergerone S, Gatti S, Gallo S, Ponzetto A, Ponzetto C and Crepaldi T: MicroRNAs in myocardial ischemia: Identifying new targets and tools for treating heart disease. New frontiers for miR-medicine. Cell Mol Life Sci. 71:1439–1452. 2014. View Article : Google Scholar
4	Port JD and Sucharov C: Role of microRNAs in cardiovascular disease: Therapeutic challenges and potentials. J Cardiovasc Pharmacol. 56:444–453. 2010. View Article : Google Scholar : PubMed/NCBI
5	Xia W, Ma X, Li X, Dong H, Yi J, Zeng W and Yang Z: miR-153 inhibits epithelial-to-mesenchymal transition in hepatocellular carcinoma by targeting Snail. Oncol Rep. 34:655–662. 2015.PubMed/NCBI
6	Zhou J, Xie M, Shi Y, Luo B, Gong G, Li J, Wang J, Zhao W, Zi Y, Wu X and Wen J: MicroRNA-153 functions as a tumor suppressor by targeting SET7 and ZEB2 in ovarian cancer cells. Oncol Rep. 34:111–120. 2015.PubMed/NCBI
7	Hua HW, Jiang F, Huang Q, Liao Z and Ding G: MicroRNA-153 promotes Wnt/β-catenin activation in hepatocellular carcinoma through suppression of WWOX. Oncotarget. 6:3840–3847. 2015. View Article : Google Scholar : PubMed/NCBI
8	Shan N, Shen L, Wang J, He D and Duan C: MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19. Biochem Biophys Res Commun. 456:385–391. 2015. View Article : Google Scholar
9	Carroll RG, Hollville E and Martin SJ: Parkin sensitizes toward apoptosis induced by mitochondrial depolarization through promoting degradation of Mcl-1. Cell Rep. 9:1538–1553. 2014. View Article : Google Scholar : PubMed/NCBI
10	Thomas RL, Roberts DJ, Kubli DA, Lee Y, Quinsay MN, Owens JB, Fischer KM, Sussman MA, Miyamoto S and Gustafsson ÅB: Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 27:1365–1377. 2013. View Article : Google Scholar : PubMed/NCBI
11	Jokinen E and Koivunen JP: Bcl-xl and Mcl-1 are the major determinants of the apoptotic response to dual PI3K and MEK blockage. Int J Oncol. 47:1103–1110. 2015.PubMed/NCBI
12	Cerella C, Muller F, Gaigneaux A, Radogna F, Viry E, Chateauvieux S, Dicato M and Diederich M: Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450. Cell Death Dis. 6:e17822015. View Article : Google Scholar : PubMed/NCBI
13	Varadarajan S, Poornima P, Milani M, Gowda K, Amin S, Wang HG and Cohen GM: Maritoclax and dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and -independent manner. Oncotarget. 6:12668–12681. 2015. View Article : Google Scholar : PubMed/NCBI
14	Wang X, Bathina M, Lynch J, Koss B, Calabrese C, Frase S, Schuetz JD, Rehg JE and Opferman JT: Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev. 27:1351–1364. 2013. View Article : Google Scholar : PubMed/NCBI
15	Li L, Xu J, He L, Peng L, Zhong Q, Chen L and Jiang Z: The role of autophagy in cardiac hypertrophy. Acta Biochim Biophys Sin. 2016.
16	Jia Z, Liu Y, Su H, Li M, Zhang M, Zhu Y, Li T, Fang Y and Liang S: Safflower extract inhibiting apoptosis by inducing autophagy in myocardium derived H9C2 cell. Int J Clin Exp Med. 8:20254–20262. 2015.
17	Schiattarella GG and Hill JA: Therapeutic targeting of autophagy in cardiovascular disease. J Mol Cell Cardiol. 2015.PubMed/NCBI
18	Wang K, Liu F, Zhou LY, Ding SL, Long B, Liu CY, Sun T, Fan YY, Sun L and Li PF: miR-874 regulates myocardial necrosis by targeting caspase-8. Cell Death Dis. 4:e7092013. View Article : Google Scholar : PubMed/NCBI
19	Xu J, Liao X and Wong C: Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG. Int J Cancer. 126:1029–1035. 2010.
20	Wang K, Liu CY, Zhang XJ, Feng C, Zhou LY, Zhao Y and Li PF: miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury. Cell Death Differ. 22:1058–1068. 2015. View Article : Google Scholar :
21	Xu C, Hu Y, Hou L, Ju J, Li X, Du N, Guan X, Liu Z, Zhang T, Qin W, et al: β-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression. J Mol Cell Cardiol. 75:111–121. 2014. View Article : Google Scholar : PubMed/NCBI
22	Bai Z, Sun J, Wang X, Wang H, Pei H and Zhang Z: MicroRNA-153 is a prognostic marker and inhibits cell migration and invasion by targeting SNAI1 in human pancreatic ductal adenocarcinoma. Oncol Rep. 34:595–602. 2015.PubMed/NCBI
23	Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, et al: The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 13:619–624. 2007. View Article : Google Scholar : PubMed/NCBI
24	Dutta D, Xu J, Kim JS, Dunn WA Jr and Leeuwenburgh C: Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity. Autophagy. 9:328–344. 2013. View Article : Google Scholar : PubMed/NCBI
25	Wang JX, Jiao JQ, Li Q, Long B, Wang K, Liu JP, Li YR and Li PF: miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med. 17:71–78. 2011. View Article : Google Scholar
26	Zhao Y, Samal E and Srivastava D: Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 436:214–220. 2005. View Article : Google Scholar : PubMed/NCBI