MiR-31a-5p aggravates apoptosis in myocardial ischemia by targeting HIF-1α_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LU Kongli ¹ , LI Xueqing ¹ , DU Ling ² , XUE Song ¹ ,  LIAN Feng ¹

1. Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China;
2. Department of Central Laboratory, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China;

Corresponding author：

LIAN Feng, Email: dr.lianfeng@hotmail.com

Keywords：

MiR-31a-5p; cardiomyocytes; hypoxia-inducible factor-1α; myocardial hypoxia; apoptosis; experimental study

DOI：

10.7507/1007-4848.202209049

Video：

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Objective To investigate the expression of miR-31a-5p in myocardial infarction (MI) mice and its potential mechanism. Methods A dataset was downloaded from the gene expression database, and miR-31a-5p and its predicted target gene hypoxia-inducible factor-1α (HIF-1α) were screened using bioinformatics methods. The MI model was established by ligating the left anterior descending branch of the coronary artery in C57BL/6J male mice which were randomly divided into sham and MI groups (n=6 in each group). The in vitro hypoxic cell model was induced by treatment of H9c2 cells with cobalt chloride (CoCl₂) and divided into a control group, a model group, a NC group, a miR-31a-5p mimic group and a miR-31a-5p inhibitor group. The degree of myocardial tissue fibrosis was stained by Masson and analyzed. The expression levels of miR-31a-5p and HIF-1α mRNA in mouse myocardial tissues and H9c2 cells were detected by qRT-PCR. Western blotting was used to detect the expression levels of B-cell lymphoma 2 (Bcl-2), cleaved-caspase 3 apoptotic protein in mouse myocardial tissues and HIF-1α and apoptotic protein in H9c2 cells, respectively. The dual luciferase reporter gene assay was used to verify the targeting relationship between miR-31a-5p and HIF-1α. Results Masson staining showed significantly increased fibrosis in MI mice (P<0.000 1); miR-31a-5p, cleaved-caspase 3 were significantly elevated and Bcl-2 was decreased in MI mice and CoCl₂ treated H9c2 (P<0.05). The results of dual luciferase reporter assay showed that the relative luciferase activity of miR-31a-5p mimic cotransfected with HIF-1α-3'-UTR WT plasmid was reduced (P<0.000 1); miR-31a-5p mimic decreased HIF-1α expression and increased apoptotic protein levels in CoCl₂ induced H9c2 cells (both P<0.05), while miR-31a-5p exerted the opposite effect. Conclusion miR-31a-5p can aggravate apoptosis in myocardial ischemia by targeting HIF-1α.

Citation： LU Kongli, LI Xueqing, DU Ling, XUE Song, LIAN Feng. MiR-31a-5p aggravates apoptosis in myocardial ischemia by targeting HIF-1α. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2024, 31(5): 782-790. doi: 10.7507/1007-4848.202209049 Copy

1.	Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: A report from the American Heart Association. Circulation, 2020, 141(9): e139-e596.
2.	Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol, 2018, 72(18): 2231-2264.
3.	Wang J, Dong G, Chi W, et al. MiR-96 promotes myocardial infarction-induced apoptosis by targeting XIAP. Biomed Pharmacother, 2021, 138: 111208.
4.	Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol, 2015, 5(4): 1841-1875.
5.	Gao F, Kataoka M, Liu N, et al. Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction. Nat Commun, 2019, 10(1): 1802.
6.	Cheng XJ, Li L, Xin BQ. MiR-124 Regulates the inflammation and apoptosis in myocardial infarction rats by targeting STAT3. Cardiovasc Toxicol, 2021, 21(9): 710-720.
7.	Li X, Long J, Zong L, et al. ZNF561-AS1 regulates cell proliferation and apoptosis in myocardial infarction through miR-223-3p/NLRP3 axis. Cell Transplant, 2022, 31: 9636897221077928.
8.	Gou L, Xue C, Tang X, et al. Inhibition of Exo-miR-19a-3p derived from cardiomyocytes promotes angiogenesis and improves heart function in mice with myocardial infarction via targeting HIF-1α. Aging (Albany NY), 2020, 12(23): 23609-23618.
9.	Cheng H, Chang S, Xu R, et al. Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis. Stem Cell Res Ther, 2020, 11(1): 224.
10.	Wei YJ, Wang JF, Cheng F, et al. miR-124-3p targeted SIRT1 to regulate cell apoptosis, inflammatory response, and oxidative stress in acute myocardial infarction in rats via modulation of the FGF21/CREB/PGC1α pathway. J Physiol Biochem, 2021, 77(4): 577-587.
11.	Cai J, Wang X, Liao W, et al. Silencing lncRNA 93358 inhibits the apoptosis of myocardial cells in myocardial infarction rats by inducing the expression of SLC8A1. Biomed Res Int, 2022, 2022: 1138709.
12.	Liao B, Dong S, Xu Z, et al. MiR-19b-3p regulated by BC002059/ABHD10 axis promotes cell apoptosis in myocardial infarction. Biol Direct, 2022, 17(1): 20.
13.	Xu R, Shen X, Si Y, et al. MicroRNA-31a-5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment. Aging Cell, 2018, 17(4): e12794.
14.	Xiao J, Liu H, Cretoiu D, et al. miR-31a-5p promotes postnatal cardiomyocyte proliferation by targeting RhoBTB1. Exp Mol Med, 2017, 49(10): e386.
15.	Semenza GL. Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol, 2014, 76: 39-56.
16.	Li X, Zhang Q, Nasser MI, et al. Oxygen homeostasis and cardiovascular disease: A role for HIF? Biomed Pharmacother, 2020, 128: 110338.
17.	Datta Chaudhuri R, Banik A, Mandal B, et al. Cardiac-specific overexpression of HIF-1α during acute myocardial infarction ameliorates cardiomyocyte apoptosis via differential regulation of hypoxia-inducible pro-apoptotic and anti-oxidative genes. Biochem Biophys Res Commun, 2021, 537: 100-108.
18.	Gao E, Lei YH, Shang X, et al. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res, 2010, 107(12): 1445-1453.
19.	Yu G, Liu P, Shi Y, et al. Stimulation of endothelial progenitor cells by microRNA-31a-5p to induce endothelialization in an aneurysm neck after coil embolization by modulating the Axin1-mediated β-catenin/vascular endothelial growth factor pathway. J Neurosurg, 2019: 1-9.
20.	Yan C, Chen J, Wang C, et al. Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis. Drug Deliv, 2022, 29(1): 214-228.
21.	Bi J, Liu H, Cai Z, et al. Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis. Aging (Albany NY), 2018, 10(8): 1964-1976.
22.	Peng H, Wang L, Su Q, et al. MiR-31-5p promotes the cell growth, migration and invasion of colorectal cancer cells by targeting NUMB. Biomed Pharmacother, 2019, 109: 208-216.
23.	Li Y, Quan J, Chen F, et al. MiR-31-5p acts as a tumor suppressor in renal cell carcinoma by targeting cyclin-dependent kinase 1 (CDK1). Biomed Pharmacother, 2019, 111: 517-526.
24.	Feng Q, Tian T, Liu J, et al. Deregulation of microRNA-31a-5p is involved in the development of primary hypertension by suppressing apoptosis of pulmonary artery smooth muscle cells via targeting TP53. Int J Mol Med, 2018, 42(1): 290-298.
25.	Zhou Y, Deng M, Su J, et al. The role of miR-31-5p in the development of intervertebral disc degeneration and its therapeutic potential. Front Cell Dev Biol, 2021, 9: 633974.
26.	Günter J, Ruiz-Serrano A, Pickel C, et al. The functional interplay between the HIF pathway and the ubiquitin system - more than a one-way road. Exp Cell Res, 2017, 356(2): 152-159.
27.	Liu A, Xu J. Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis. Clin Transl Oncol, 2021, 23(9): 1905-1914.
28.	Liang S, Ning R, Zhang J, et al. MiR-939-5p suppresses PM2.5-induced endothelial injury via targeting HIF-1α in HAECs. Nanotoxicology, 2021, 15(5): 706-720.

1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: A report from the American Heart Association. Circulation, 2020, 141(9): e139-e596.
2. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol, 2018, 72(18): 2231-2264.
3. Wang J, Dong G, Chi W, et al. MiR-96 promotes myocardial infarction-induced apoptosis by targeting XIAP. Biomed Pharmacother, 2021, 138: 111208.
4. Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol, 2015, 5(4): 1841-1875.
5. Gao F, Kataoka M, Liu N, et al. Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction. Nat Commun, 2019, 10(1): 1802.
6. Cheng XJ, Li L, Xin BQ. MiR-124 Regulates the inflammation and apoptosis in myocardial infarction rats by targeting STAT3. Cardiovasc Toxicol, 2021, 21(9): 710-720.
7. Li X, Long J, Zong L, et al. ZNF561-AS1 regulates cell proliferation and apoptosis in myocardial infarction through miR-223-3p/NLRP3 axis. Cell Transplant, 2022, 31: 9636897221077928.
8. Gou L, Xue C, Tang X, et al. Inhibition of Exo-miR-19a-3p derived from cardiomyocytes promotes angiogenesis and improves heart function in mice with myocardial infarction via targeting HIF-1α. Aging (Albany NY), 2020, 12(23): 23609-23618.
9. Cheng H, Chang S, Xu R, et al. Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis. Stem Cell Res Ther, 2020, 11(1): 224.
10. Wei YJ, Wang JF, Cheng F, et al. miR-124-3p targeted SIRT1 to regulate cell apoptosis, inflammatory response, and oxidative stress in acute myocardial infarction in rats via modulation of the FGF21/CREB/PGC1α pathway. J Physiol Biochem, 2021, 77(4): 577-587.
11. Cai J, Wang X, Liao W, et al. Silencing lncRNA 93358 inhibits the apoptosis of myocardial cells in myocardial infarction rats by inducing the expression of SLC8A1. Biomed Res Int, 2022, 2022: 1138709.
12. Liao B, Dong S, Xu Z, et al. MiR-19b-3p regulated by BC002059/ABHD10 axis promotes cell apoptosis in myocardial infarction. Biol Direct, 2022, 17(1): 20.
13. Xu R, Shen X, Si Y, et al. MicroRNA-31a-5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment. Aging Cell, 2018, 17(4): e12794.
14. Xiao J, Liu H, Cretoiu D, et al. miR-31a-5p promotes postnatal cardiomyocyte proliferation by targeting RhoBTB1. Exp Mol Med, 2017, 49(10): e386.
15. Semenza GL. Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol, 2014, 76: 39-56.
16. Li X, Zhang Q, Nasser MI, et al. Oxygen homeostasis and cardiovascular disease: A role for HIF? Biomed Pharmacother, 2020, 128: 110338.
17. Datta Chaudhuri R, Banik A, Mandal B, et al. Cardiac-specific overexpression of HIF-1α during acute myocardial infarction ameliorates cardiomyocyte apoptosis via differential regulation of hypoxia-inducible pro-apoptotic and anti-oxidative genes. Biochem Biophys Res Commun, 2021, 537: 100-108.
18. Gao E, Lei YH, Shang X, et al. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res, 2010, 107(12): 1445-1453.
19. Yu G, Liu P, Shi Y, et al. Stimulation of endothelial progenitor cells by microRNA-31a-5p to induce endothelialization in an aneurysm neck after coil embolization by modulating the Axin1-mediated β-catenin/vascular endothelial growth factor pathway. J Neurosurg, 2019: 1-9.
20. Yan C, Chen J, Wang C, et al. Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis. Drug Deliv, 2022, 29(1): 214-228.
21. Bi J, Liu H, Cai Z, et al. Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis. Aging (Albany NY), 2018, 10(8): 1964-1976.
22. Peng H, Wang L, Su Q, et al. MiR-31-5p promotes the cell growth, migration and invasion of colorectal cancer cells by targeting NUMB. Biomed Pharmacother, 2019, 109: 208-216.
23. Li Y, Quan J, Chen F, et al. MiR-31-5p acts as a tumor suppressor in renal cell carcinoma by targeting cyclin-dependent kinase 1 (CDK1). Biomed Pharmacother, 2019, 111: 517-526.
24. Feng Q, Tian T, Liu J, et al. Deregulation of microRNA-31a-5p is involved in the development of primary hypertension by suppressing apoptosis of pulmonary artery smooth muscle cells via targeting TP53. Int J Mol Med, 2018, 42(1): 290-298.
25. Zhou Y, Deng M, Su J, et al. The role of miR-31-5p in the development of intervertebral disc degeneration and its therapeutic potential. Front Cell Dev Biol, 2021, 9: 633974.
26. Günter J, Ruiz-Serrano A, Pickel C, et al. The functional interplay between the HIF pathway and the ubiquitin system - more than a one-way road. Exp Cell Res, 2017, 356(2): 152-159.
27. Liu A, Xu J. Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis. Clin Transl Oncol, 2021, 23(9): 1905-1914.
28. Liang S, Ning R, Zhang J, et al. MiR-939-5p suppresses PM2.5-induced endothelial injury via targeting HIF-1α in HAECs. Nanotoxicology, 2021, 15(5): 706-720.

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MiR-31a-5p aggravates apoptosis in myocardial ischemia by targeting HIF-1α

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