MicroRNA‑126 and VEGF enhance the function of endothelial progenitor cells in acute myocardial infarction

Zhang,Ying; Xu,Yi; Zhou,Ke; Kao,Guoying; Xiao,Jun

doi:10.3892/etm.2021.11065

MicroRNA‑126 and VEGF enhance the function of endothelial progenitor cells in acute myocardial infarction

Authors:
- Ying Zhang
- Yi Xu
- Ke Zhou
- Guoying Kao
- Jun Xiao
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Affiliations: Department of Cardiovascular Medicine, Chongqing Emergency Medical Center (Fourth People's Hospital of Chongqing), Chongqing 400014, P.R. China
Published online on: December 14, 2021 https://doi.org/10.3892/etm.2021.11065
Article Number: 142
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Previous studies have found that microRNA‑126 (miR‑126) overexpression can exert beneficial effects on endothelial function and angiogenesis. The role of miR‑126 was previously reported to be by directly limiting the activities of negative regulators of the vascular endothelial growth factor (VEGF) pathway, such as PI3K regulation subunit 2 (PIK3R2). The aim of the present study was to investigate the role of the miR‑126/PIK3R2/VEGF axis in endothelial progenitor cells (EPCs) under hypoxic conditions. An in vitro hypoxia model in EPCs was established by exposing EPCs to hypoxia (O2/N2/CO2, 1/94/5) for 72 h, before reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analyzes were used to measure miR‑126 and PIK3R2 expression in EPCs. The proliferation, migration and tube‑forming ability of the transfected cells were measured using MTT, Transwell and tube formation assays, respectively. miR‑126 expression was found to be lower in EPCs in the hypoxia group compared with that in the control group (P<0.01). The expression of PIK3R2, a direct target gene of miR‑126, was found to be higher in the hypoxia group compared with that in the control group (P<0.01). miR‑126 mimic and VEGF‑plasmid co‑transfection improved the proliferation, migration, tube‑forming ability and restored the phosphorylation of AKT in EPCs under hypoxic conditions (all P<0.01). In addition, the effects of miR‑126 mimic on hypoxia‑induced EPCs were reversed by PIK3R2‑plasmid co‑transfection, whilst the effects of VEGF‑plasmid were enhanced further by co‑transfection with the miR‑126 mimic. In conclusion, miR‑126 promoted the functions of EPCs under hypoxic conditions by negatively targeting PIK3R2, whilst the combined overexpression of miR‑126 and VEGF enhanced these aforementioned effects.

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1	Nichols M, Townsend N, Scarborough P and Rayner M: Cardiovascular disease in Europe 2014: Epidemiological update. Eur Heart J. 35:2950–2959. 2014.PubMed/NCBI View Article : Google Scholar
2	Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV and Go AS: Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med. 362:2155–2165. 2010.PubMed/NCBI View Article : Google Scholar
3	Tibaut M, Mekis D and Petrovic D: Pathophysiology of Myocardial Infarction and Acute Management strategies. Cardiovasc Hematol Agents Med Chem. 14:150–159. 2017.PubMed/NCBI View Article : Google Scholar
4	Anderson JL and Morrow DA: Acute myocardial infarction. N Engl J Med. 376:2053–2064. 2017.PubMed/NCBI View Article : Google Scholar
5	Gulati R, Behfar A, Narula J, Kanwar A, Lerman A, Cooper L and Singh M: Acute myocardial infarction in young individuals. Mayo Clin Proc. 95:136–156. 2020.PubMed/NCBI View Article : Google Scholar
6	Eltzschig HK and Eckle T: Ischemia and reperfusion-from mechanism to translation. Nat Med. 17:1391–1401. 2011.PubMed/NCBI View Article : Google Scholar
7	Arora G and Bittner V: Chest pain characteristics and gender in the early diagnosis of acute myocardial infarction. Curr Cardiol Rep. 17(5)2015.PubMed/NCBI View Article : Google Scholar
8	Shah AH, Puri R and Kalra A: Management of cardiogenic shock complicating acute myocardial infarction: A review. Clin Cardiol. 42:484–493. 2019.PubMed/NCBI View Article : Google Scholar
9	Abed MA, Ali RM, Abu Ras MM, Hamdallah FO, Khalil AA and Moser DK: Symptoms of acute myocardial infarction: A correlational study of the discrepancy between patients' expectations and experiences. Int J Nurs Stud. 52:1591–1599. 2015.PubMed/NCBI View Article : Google Scholar
10	Ndrepepa G, Keta D, Schulz S, Byrne RA, Mehilli J, Pache J, Seyfarth M, Schömig A and Kastrati A: Prognostic value of minimal blood flow restoration in patients with acute myocardial infarction after reperfusion therapy. Clin Res Cardiol. 99:13–19. 2010.PubMed/NCBI View Article : Google Scholar
11	Peters EB: Endothelial progenitor cells for the vascularization of engineered tissues. Tissue Eng Part B Rev. 24:1–24. 2018.PubMed/NCBI View Article : Google Scholar
12	Naito H, Iba T and Takakura N: Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells. Int Immunol. 32:295–305. 2020.PubMed/NCBI View Article : Google Scholar
13	Li X, Xue X, Sun Y, Chen L, Zhao T, Yang W, Chen Y and Zhang Z: MicroRNA-326-5p enhances therapeutic potential of endothelial progenitor cells for myocardial infarction. Stem Cell Res Ther. 10(323)2019.PubMed/NCBI View Article : Google Scholar
14	Huang H, Xu Z, Qi Y, Zhang W, Zhang C, Jiang M, Deng S and Wang H: Exosomes from SIRT1-Overexpressing ADSCs restore cardiac function by improving angiogenic function of EPCs. Mol Ther Nucleic Acids. 21:737–750. 2020.PubMed/NCBI View Article : Google Scholar
15	Zhou W, Zhou W, Zeng Q and Xiong J: MicroRNA-138 inhibits-hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling. Exp Ther Med. 13:1017–1024. 2017.PubMed/NCBI View Article : Google Scholar
16	Lu TX and Rothenberg ME: MicroRNA. J Allergy Clin Immunol. 141:1202–1207. 2018.PubMed/NCBI View Article : Google Scholar
17	Mohr AM and Mott JL: Overview of microRNA biology. Semin Liver Dis. 35:3–11. 2015.PubMed/NCBI View Article : Google Scholar
18	Saliminejad K, Khorram Khorshid HR, Soleymani Fard S and Ghaffari SH: An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 234:5451–5465. 2019.PubMed/NCBI View Article : Google Scholar
19	Liu B, Li J and Cairns MJ: Identifying miRNAs, targets and functions. Brief Bioinform. 15:1–19. 2014.PubMed/NCBI View Article : Google Scholar
20	Juźwik CA, S Drake S, Zhang Y, Paradis-Isler N, Sylvester A, Amar-Zifkin A, Douglas C, Morquette B, Moore CS and Fournier AE: MicroRNA dysregulation in neurodegenerative diseases: A systematic review. Prog Neurobiol. 82(101664)2019.PubMed/NCBI View Article : Google Scholar
21	Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017.PubMed/NCBI View Article : Google Scholar
22	Sun IO and Lerman LO: Urinary microRNA in kidney disease: Utility and roles. Am J Physiol Renal Physiol. 316:F785–F793. 2019.PubMed/NCBI View Article : Google Scholar
23	Wojciechowska A, Braniewska A and Kozar-Kamińska K: MicroRNA in cardiovascular biology and disease. Adv Clin Exp Med. 26:865–874. 2017.PubMed/NCBI View Article : Google Scholar
24	Johnson JL: Elucidating the contributory role of microRNA to cardiovascular diseases (a review). Vascul Pharmacol. 114:31–48. 2019.PubMed/NCBI View Article : Google Scholar
25	Sun J, Zhang Z, Ma T, Yang Z, Zhang J, Liu X, Lu D, Shen Z, Yang J and Meng Q: Endothelial progenitor cell-derived exosomes, loaded with miR-126, promoted deep vein thrombosis resolution and recanalization. Stem Cell Res Ther. 9(223)2018.PubMed/NCBI View Article : Google Scholar
26	Meng S, Cao JT, Zhang B, Zhou Q, Shen CX and Wang CQ: Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. J Mol Cell Cardiol. 53:64–72. 2012.PubMed/NCBI View Article : Google Scholar
27	Fu R and Tong JS: MiR-126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells. J Cell Mol Med. 24:7600–7608. 2020.PubMed/NCBI View Article : Google Scholar
28	Song L, Li D, Gu Y, Wen ZM, Jie J, Zhao D and Peng LP: MicroRNA-126 targeting PIK3R2 inhibits NSCLC A549 cell proliferation, migration, and invasion by regulation of PTEN/PI3K/AKT pathway. Clin Lung Cancer. 17:e65–e75. 2016.PubMed/NCBI View Article : Google Scholar
29	Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY and Srivastava D: MiR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 15:272–284. 2018.PubMed/NCBI View Article : Google Scholar
30	Ye P, Liu J, He F, Xu W and Yao K: Hypoxia-induced deregulation of miR-126 and its regulative effect on VEGF and MMP-9 expression. Int J Med Sci. 11:17–23. 2013.PubMed/NCBI View Article : Google Scholar
31	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
32	Reed GW, Rossi JE and Cannon CP: Acute myocardial infarction. Lancet. 389:197–210. 2017.PubMed/NCBI View Article : Google Scholar
33	Ratajska A, Jankowska-Steifer E, Czarnowska E, Olkowski R, Gula G, Niderla-Bielińska J, Flaht-Zabost A and Jasińska A: Vasculogenesis and its cellular therapeutic applications. Cells Tissues Organs. 203:141–152. 2017.PubMed/NCBI View Article : Google Scholar
34	Yuan JJ, Yang J, Sun SL, Zhang R and Xu YM: Endothelial progenitor cells' classification and application in neurological diseases. Tissue Eng Regen Med. 14:327–332. 2017.PubMed/NCBI View Article : Google Scholar
35	Ma Y, Jiang L, Wang L, Li Y, Liu Y, Lu W, Shi R, Zhang L, Fu Z, Qu M, et al: Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice. J Cereb Blood Flow Metab. 40:2374–2386. 2020.PubMed/NCBI View Article : Google Scholar
36	Steinle H, Golombek S, Behring A, Schlensak C, Wendel HP and Avci-Adali M: Improving the angiogenic potential of EPCs via engineering with synthetic modified mRNAs. Mol Ther Nucleic Acids. 13:387–398. 2018.PubMed/NCBI View Article : Google Scholar
37	Zeng YC, Peng LS, Zou L, Huang SF, Xie Y, Mu GP, Zeng XH, Zhou XL and Zeng YC: Protective effect and mechanism of lycopene on endothelial progenitor cells (EPCs) from type 2 diabetes mellitus rats. Biomed Pharmacother. 92:86–94. 2017.PubMed/NCBI View Article : Google Scholar
38	Klein-Soyer C, Beretz A, Cazenave JP, Driot F and Maffrand JP: Behavior of confluent endothelial cells after irradiation. Modulation of wound repair by heparin and acidic fibroblast growth factor. Biol Cell. 68:231–238. 1990.PubMed/NCBI View Article : Google Scholar
39	Chen G, Li P, Liu Z, Zeng R, Ma X, Chen Y, Xu H, Li Z and Lin H: Enrichment of miR-126 enhances the effects of endothelial progenitor cell-derived microvesicles on modulating MC3T3-E1 cell function via Erk1/2-Bcl-2 signalling pathway. Prion. 13:106–115. 2019.PubMed/NCBI View Article : Google Scholar
40	Pan Q, Zheng J, Du D, Liao X, Ma C, Yang Y, Chen Y, Zhong W and Ma X: MicroRNA-126 priming enhances functions of endothelial progenitor cells under physiological and hypoxic conditions and their therapeutic efficacy in cerebral ischemic damage. Stem Cells Int. 2018(2912347)2018.PubMed/NCBI View Article : Google Scholar
41	Xiao J, Lin HY, Zhu YY, Zhu YP and Chen LW: MiR-126 regulates proliferation and invasion in the bladder cancer BLS cell line by targeting the PIK3R2-mediated PI3K/Akt signaling pathway. Onco Targets Ther. 9:5181–5193. 2016.PubMed/NCBI View Article : Google Scholar
42	Yang WZ, Yang J, Xue LP, Xiao LB and Li Y: MiR-126 overexpression inhibits high glucose-induced migration and tube formation of rhesus macaque choroid-retinal endothelial cells by obstructing VEGFA and PIK3R2. J Diabetes Complications. 31:653–663. 2017.PubMed/NCBI View Article : Google Scholar
43	Li SN, Li P, Liu WH, Shang JJ, Qiu SL, Zhou MX and Liu HX: Danhong injection enhances angiogenesis after myocardial infarction by activating MiR-126/ERK/VEGF pathway. Biomed Pharmacother. 120(109538)2019.PubMed/NCBI View Article : Google Scholar
44	Zhang L, Ouyang P, He G, Wang X, Song D, Yang Y and He X: Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway. J Cell Mol Med. 25:2148–2162. 2021.PubMed/NCBI View Article : Google Scholar
45	Nammian P, Razban V, Tabei SMB and Asadi-Yousefabad SL: MicroRNA-126: Dual role in angiogenesis dependent diseases. Curr Pharm Des. 26:4883–4893. 2020.PubMed/NCBI View Article : Google Scholar
46	Chen X, Chen Q, Wang L and Li G: Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells. Metabolism. 62:743–752. 2013.PubMed/NCBI View Article : Google Scholar
47	Li WD, Zhou DM, Sun LL, Xiao L, Liu Z, Zhou M, Wang WB and Li XQ: LncRNA WTAPP1 promotes migration and angiogenesis of endothelial progenitor cells via MMP1 through MicroRNA 3120 and Akt/PI3K/autophagy pathways. Stem Cells. 36:1863–1874. 2018.PubMed/NCBI View Article : Google Scholar