MiR-106a targets ATG7 to inhibit autophagy and angiogenesis after myocardial infarction

Abstract

Background: Myocardial infarction (MI) is an acute condition in which the heart muscle dies due to the lack of blood supply. Previous research has suggested that autophagy and angiogenesis play vital roles in the prevention of heart failure after MI, and miR-106a is considered to be an important regulatory factor in MI. But the specific mechanism remains unknown. In this study, using cultured venous endothelial cells and a rat model of MI, we aimed to identify the potential target genes of miR-106a and discover the mechanisms of inhibiting autophagy and angiogenesis.

Methods: We first explored the biological functions of miR-106a on autophagy and angiogenesis on endothelial cells. Then we identified ATG7, which was the downstream target gene of miR-106a. The expression of miR-106a and ATG7 was investigated in the rat model of MI.

Results: We found that miR-106a inhibits the proliferation, cell cycle, autophagy and angiogenesis, but promoted the apoptosis of vein endothelial cells. Moreover, ATG7 was identified as the target of miR-106a, and ATG7 rescued the inhibition of autophagy and angiogenesis by miR-106a. The expression of miR-106a in the rat model of MI was decreased but the expression of ATG7 was increased in the infarction areas.

Conclusion Our results indicate that miR-106a may inhibit autophagy and angiogenesis by targeting ATG7. This mechanism may be a potential therapeutic treatment for MI.

Keywords

angiogenesis / ATG7 / autophagy / miR-106a / miRNAs / myocardial infarction

References

[1] Gracia E, Hamid A, Butler J. Timely Management of new-Onset Heart Failure. Circulation. 2019;140:621-623.

[2] Benson CE, Southgate L. The DOCK protein family in vascular development and disease. Angiogenesis. 2021;24:417-433.

[3] Guillamat-Prats R. The role of MSC in wound healing, scarring and regeneration. Cells. 2021;10:1729.

[4] Sajib S, Zahra FT, Lionakis MS, German NA, Mikelis CM. Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis. 2018;21:1-14.

[5] Huang P, Wang L, Li Q, et al. Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19. Cardiovasc Res. 2020;116:353-367.

[6] Zou J, Fei Q, Xiao H, et al. VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy. J Cell Physiol. 2019;234:17690-17703.

[7] Wang K, Liu CY, Zhou LY, et al. APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun. 2015;6:6779.

[8] Zhou M, Zou YG, Xue YZ, et al. Long non-coding RNA H19 protects acute myocardial infarction through activating autophagy in mice. Eur Rev Med Pharmacol Sci. 2018;22:5647-5651.

[9] El Agaty AS, Nassef NA, Abou-Bakr DA, Hanafy AA. Chronic activation of cardiac Atg-5 and pancreatic Atg-7 by intermittent fasting alleviates acute myocardial infarction in old rats. Egypt Heart J. 2022;74:31.

[10] Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11:597-610.

[11] Pan YJ, Zhuang Y, Zheng JN, Pei DS. MiR-106a: promising biomarker for cancer. Bioorg Med Chem Lett. 2016;26:5373-5377.

[12] He L, Chu Y, Yang J, et al. Activation of autophagic flux maintains mitochondrial homeostasis during cardiac ischemia/reperfusion injury. Cells. 2022;11:2111.

[13] Wicik Z, Czajka P, Eyileten C, et al. The role of miRNAs in regulation of platelet activity and related diseases – a bioinformatic analysis. Platelets. 2022;33:1052-1064.

[14] Bye A, Røsjø H, Nauman J, et al. Circulating microRNAs predict future fatal myocardial infarction in healthy individuals – the HUNT study. J Mol Cell Cardiol. 2016;97:162-168.

[15] Rothschild SI, Gautschi O, Batliner J, Gugger M, Fey MF, Tschan MP. MicroRNA-106a targets autophagy and enhances sensitivity of lung cancer cells to Src inhibitors. Lung Cancer. 2017;107:73-83.

[16] Hao H, Xia G, Wang C, Zhong F, Liu L, Zhang D. miR-106a suppresses tumor cells death in colorectal cancer through targeting ATG7. Med Mol Morphol. 2017;50:76-85.

[17] Gu H, Liu Z, Zhou L. Roles of miR-17-92 cluster in cardiovascular development and common diseases. Biomed Res Int. 2017;2017:9102909.

[18] Zhou M, Cai J, Tang Y, Zhao Q. MiR-17-92 cluster is a novel regulatory gene of cardiac ischemic/reperfusion injury. Med Hypotheses. 2013;81:108-110.

[19] Gao WQ, Hu XM, Zhang Q, et al. Downregulation of circFASTKD1 ameliorates myocardial infarction by promoting angiogenesis. Aging (Albany NY). 2020;13:3588-3604.

[20] Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke Statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143:e254-e273.

[21] Zheng Y, Zhu K, Wang G. miR-106a-5p carried by tumor-derived extracellular vesicles promotes the invasion and metastasis of ovarian cancer by targeting KLF6. Clin Exp Metastasis. 2022;39:603-621.

[22] Jin L, Pan Y, Li Q, Li J, Wang Z. Elabela gene therapy promotes angiogenesis after myocardial infarction. J Cell Mol Med. 2021;25:8537-8545.

[23] Wu X, Reboll MR, Korf-Klingebiel M, Wollert KC. Angiogenesis after acute myocardial infarction. Cardiovasc Res. 2021;117:1257-1273.

[24] Badimon L, Borrell M. Microvasculature recovery by angiogenesis after myocardial infarction. Curr Pharm Des. 2018;24:2967-2973.

[25] Dudenbostel T. Correction to: heart disease and stroke Statistics-2022 update: a report from the American Heart Association. Circulation. 2022;146:e141.

[26] Gabisonia K, Prosdocimo G, Aquaro GD, et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569:418-422.

[27] Xiao Y, Zhao J, Tuazon JP, Borlongan CV, Yu G. MicroRNA-133a and myocardial infarction. Cell Transplant. 2019;28:831-838.

[28] Zhang D, Ning J, Ramprasath T, et al. Kynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis. Nat Commun. 2022;13:6371.

[29] Cuevas A, Saavedra N, Cavalcante MF, Salazar LA, Abdalla DS. Identification of microRNAs involved in the modulation of pro-angiogenic factors in atherosclerosis by a polyphenol-rich extract from propolis. Arch Biochem Biophys. 2014;557:28-35.

[30] Ma J, Wang W, Azhati B, Wang Y, Tusong H. miR-106a-5p functions as a tumor suppressor by targeting VEGFA in renal cell carcinoma. Dis Markers. 2020;2020:8837941.

[31] Hu Y, Xu R, He Y, et al. Downregulation of microRNA106a5p alleviates oxLDLmediated endothelial cell injury by targeting STAT3. Mol Med Rep. 2020;22:783-791.

[32] Du J, Li Y, Zhang C. Application of autophagy in cardiovascular diseases. Adv Exp Med Biol. 2020;1207:265.

[33] Bravo-San PJ, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812-1824.

[34] Gatica D, Chiong M, Lavandero S, Klionsky DJ. The role of autophagy in cardiovascular pathology. Cardiovasc Res. 2022;118:934-950.

[35] Zhang L, Zhang Y, Yu F, Li X, Gao H, Li P. The circRNA-miRNA/RBP regulatory network in myocardial infarction. Front Pharmacol. 2022;13:941123.

[36] Ajoolabady A, Chiong M, Lavandero S, Klionsky DJ, Ren J. Mitophagy in cardiovascular diseases: molecular mechanisms, pathogenesis, and treatment. Trends Mol Med. 2022;28:836-849.

[37] Niu C, Chen Z, Kim KT, et al. Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway. Autophagy. 2019;15:843-870.

[38] Zhu Z, Li J, Tong R, Zhang X, Yu B. miR-149 alleviates ox-LDL-induced endothelial cell injury by promoting autophagy through Akt/mTOR pathway. Cardiol Res Pract. 2021;2021:9963258.

[39] Guo H, Ding H, Yan Y, et al. Intermittent hypoxia-induced autophagy via AMPK/mTOR signaling pathway attenuates endothelial apoptosis and dysfunction in vitro. Sleep Breath. 2021;25:1859-1865.

[40] Zhao F, Satyanarayana G, Zhang Z, Zhao J, Ma XL, Wang Y. Endothelial autophagy in coronary microvascular dysfunction and cardiovascular disease. Cells. 2022;11:2081.

[41] Zhou Y, Zhang Y, Li Y, et al. MicroRNA-106a-5p promotes the proliferation, autophagy and migration of lung adenocarcinoma cells by targeting LKB1/AMPK. Exp Ther Med. 2021;22:1422.

[42] Tang J, Hu P, Zhou S, Zhou T, Li X, Zhang L. Lymphoma cell-derived extracellular vesicles inhibit autophagy and apoptosis to promote lymphoma cell growth via the microRNA-106a/Beclin1 axis. Cell Cycle. 2022;21:1280-1293.

[43] Li R, Lu Y, Zhang Q, et al. Piperine promotes autophagy flux by P2RX4 activation in SNCA/alpha-synuclein-induced Parkinson disease model. Autophagy. 2022;18:559-575.

[44] Zeng H, He D, Xie H, et al. H19 regulates angiogenic capacity of extravillous trophoblasts by H19/miR-106a-5p/VEGFA axis. Arch Gynecol Obstet. 2020;301:671-679.

[45] Behera J, Kumar A, Voor MJ, Tyagi N. Exosomal lncRNA-H19 promotes osteogenesis and angiogenesis through mediating Angpt1/Tie2-NO signaling in CBS-heterozygous mice. Theranostics. 2021;11:7715-7734.

[46] Salgado-Garcia R, Coronel-Hernández J, Delgado-Waldo I, et al. Negative regulation of ULK1 by microRNA-106a in autophagy induced by a triple drug combination in colorectal cancer cells in vitro. Genes. 2021;12:245.

[47] Collier JJ, Olahova M, McWilliams TG, Taylor RW. ATG7 safeguards human neural integrity. Autophagy. 2021;17:2651-2653.

[48] Mizushima N, Noda T, Yoshimori T, et al. A protein conjugation system essential for autophagy. Nature. 1998;395:395-398.

[49] Galluzzi L, Baehrecke EH, Ballabio A, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36:1811-1836.

[50] Liu K, Hong D, Zhang F, et al. MicroRNA-106a inhibits autophagy process and antimicrobial responses by targeting ULK1, ATG7, and ATG16L1 during mycobacterial infection. Front Immunol. 2020;11:610021.

[51] Hundahl LA, Tfelt-Hansen J, Jespersen T. Rat models of ventricular fibrillation following acute myocardial infarction. J Cardiovasc Pharmacol Ther. 2017;22:514-528.

[52] Ji Z, Wang C, Tong Q. Role of miRNA-324-5p-modified adipose-derived stem cells in post-myocardial infarction repair. Int J Stem Cells. 2021;14:298-309.

[53] Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined–a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36:959-969.

[54] Li F, Long TY, Bi SS, Sheikh SA, Zhang CL. circPAN3 exerts a profibrotic role via sponging miR-221 through FoxO3/ATG7-activated autophagy in a rat model of myocardial infarction. Life Sci. 2020;257:118015.

[55] Hao L, Wang J, Bi SJ, Cheng C. Upregulation of Long noncoding RNA FGD5-AS1 ameliorates myocardial ischemia/reperfusion injury via MicroRNA-106a-5p and MicroRNA-106b-5p. J Cardiovasc Pharmacol. 2021;78:e45-e54.

[56] Han ZL, Wang HQ, Zhang TS, He YX, Zhou H. Up-regulation of exosomal miR-106a may play a significant role in abdominal aortic aneurysm by inducing vascular smooth muscle cell apoptosis and targeting TIMP-2, an inhibitor of metallopeptidases that suppresses extracellular matrix degradation. Eur Rev Med Pharmacol. 2020;24:8087.

RIGHTS & PERMISSIONS

2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.