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Published in: BMC Cardiovascular Disorders 1/2021

Open Access 01-12-2021 | Research article

microRNA-130a-5p suppresses myocardial ischemia reperfusion injury by downregulating the HMGB2/NF-κB axis

Authors: Yong Li, Hongbo Zhang, Zhanhu Li, Xiaoju Yan, Yuan Li, Shuai Liu

Published in: BMC Cardiovascular Disorders | Issue 1/2021

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Abstract

Background

Myocardial ischemia reperfusion injury (MIRI) is defined as tissue injury in the pathological process of progressive aggravation in ischemic myocardium after the occurrence of acute coronary artery occlusion. Research has documented the involvement of microRNAs (miRs) in MIRI. However, there is obscure information about the role of miR-130a-5p in MIRI. Herein, this study aims to investigate the effect of miR-130a-5p on MIRI.

Methods

MIRI mouse models were established. Then, the cardiac function and hemodynamics were detected using ultrasonography and multiconductive physiological recorder. Functional assays in miR-130a-5p were adopted to test the degrees of oxidative stress, mitochondrial functions, inflammation and apoptosis. Hematoxylin and eosin (HE) staining was performed to validate the myocardial injury in mice. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to assess the expression patterns of miR-130a-5p, high mobility group box (HMGB)2 and NF-κB. Then, dual-luciferase reporter gene assay was performed to elucidate the targeting relation between miR-130a-5p and HMGB2.

Results

Disrupted structural arrangement in MIRI mouse models was evident from HE staining. RT-qPCR revealed that overexpressed miR-130a-5p alleviated MIRI, MIRI-induced oxidative stress and mitochondrial disorder in the mice. Next, the targeting relation between miR-130a-5p and HMGB2 was ascertained. Overexpressed HMGB2 annulled the protective effects of miR-130a-5p in MIRI mice. Additionally, miR-130a-5p targets HMGB2 to downregulate the nuclear factor kappa-B (NF-κB) axis, mitigating the inflammatory injury induced by MIRI.

Conclusion

Our study demonstrated that miR-130a-5p suppresses MIRI by down-regulating the HMGB2/NF-κB axis. This investigation may provide novel insights for development of MIRI treatments.
Literature
1.
go back to reference Halladin NL. Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries. Dan Med J. 2015;62(4):B5054.PubMed Halladin NL. Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries. Dan Med J. 2015;62(4):B5054.PubMed
2.
go back to reference Ndrepepa G, Colleran R, Kastrati A. Reperfusion injury in ST-segment elevation myocardial infarction: the final frontier. Coron Artery Dis. 2017;28(3):253–62.CrossRef Ndrepepa G, Colleran R, Kastrati A. Reperfusion injury in ST-segment elevation myocardial infarction: the final frontier. Coron Artery Dis. 2017;28(3):253–62.CrossRef
3.
go back to reference Shi J, Dai W, Kloner RA. Therapeutic hypothermia reduces the inflammatory response following ischemia/reperfusion injury in rat hearts. Ther Hypothermia Temp Manag. 2017;7(3):162–70.CrossRef Shi J, Dai W, Kloner RA. Therapeutic hypothermia reduces the inflammatory response following ischemia/reperfusion injury in rat hearts. Ther Hypothermia Temp Manag. 2017;7(3):162–70.CrossRef
4.
go back to reference Ding J, Yang Z, Ma H, Zhang H. Mitochondrial aldehyde dehydrogenase in myocardial ischemic and ischemia-reperfusion injury. Adv Exp Med Biol. 2019;1193:107–20.CrossRef Ding J, Yang Z, Ma H, Zhang H. Mitochondrial aldehyde dehydrogenase in myocardial ischemic and ischemia-reperfusion injury. Adv Exp Med Biol. 2019;1193:107–20.CrossRef
5.
go back to reference Thummasorn S, Apaijai N, Kerdphoo S, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N. Humanin exerts cardioprotection against cardiac ischemia/reperfusion injury through attenuation of mitochondrial dysfunction. Cardiovasc Ther. 2016;34(6):404–14.CrossRef Thummasorn S, Apaijai N, Kerdphoo S, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N. Humanin exerts cardioprotection against cardiac ischemia/reperfusion injury through attenuation of mitochondrial dysfunction. Cardiovasc Ther. 2016;34(6):404–14.CrossRef
6.
go back to reference Mokhtari-Zaer A, Marefati N, Atkin SL, Butler AE, Sahebkar A. The protective role of curcumin in myocardial ischemia-reperfusion injury. J Cell Physiol. 2018;234(1):214–22.CrossRef Mokhtari-Zaer A, Marefati N, Atkin SL, Butler AE, Sahebkar A. The protective role of curcumin in myocardial ischemia-reperfusion injury. J Cell Physiol. 2018;234(1):214–22.CrossRef
7.
go back to reference Makhdoumi P, Roohbakhsh A, Karimi G. MicroRNAs regulate mitochondrial apoptotic pathway in myocardial ischemia-reperfusion-injury. Biomed Pharmacother. 2016;84:1635–44.CrossRef Makhdoumi P, Roohbakhsh A, Karimi G. MicroRNAs regulate mitochondrial apoptotic pathway in myocardial ischemia-reperfusion-injury. Biomed Pharmacother. 2016;84:1635–44.CrossRef
8.
go back to reference Siebert V, Allencherril J, Ye Y, Wehrens XHT, Birnbaum Y. The role of non-coding RNAs in ischemic myocardial reperfusion injury. Cardiovasc Drugs Ther. 2019;33(4):489–98.CrossRef Siebert V, Allencherril J, Ye Y, Wehrens XHT, Birnbaum Y. The role of non-coding RNAs in ischemic myocardial reperfusion injury. Cardiovasc Drugs Ther. 2019;33(4):489–98.CrossRef
9.
go back to reference Zheng T, Shi Y, Zhang J, Peng J, Zhang X, Chen K, et al. MiR-130a exerts neuroprotective effects against ischemic stroke through PTEN/PI3K/AKT pathway. Biomed Pharmacother. 2019;117:109117.CrossRef Zheng T, Shi Y, Zhang J, Peng J, Zhang X, Chen K, et al. MiR-130a exerts neuroprotective effects against ischemic stroke through PTEN/PI3K/AKT pathway. Biomed Pharmacother. 2019;117:109117.CrossRef
10.
go back to reference Lu C, Wang X, Ha T, Hu Y, Liu L, Zhang X, et al. Attenuation of cardiac dysfunction and remodeling of myocardial infarction by microRNA-130a are mediated by suppression of PTEN and activation of PI3K dependent signaling. J Mol Cell Cardiol. 2015;89(Pt A):87–97.CrossRef Lu C, Wang X, Ha T, Hu Y, Liu L, Zhang X, et al. Attenuation of cardiac dysfunction and remodeling of myocardial infarction by microRNA-130a are mediated by suppression of PTEN and activation of PI3K dependent signaling. J Mol Cell Cardiol. 2015;89(Pt A):87–97.CrossRef
11.
go back to reference Jin F, Xing J. Circulating miR-126 and miR-130a levels correlate with lower disease risk, disease severity, and reduced inflammatory cytokine levels in acute ischemic stroke patients. Neurol Sci. 2018;39(10):1757–65.CrossRef Jin F, Xing J. Circulating miR-126 and miR-130a levels correlate with lower disease risk, disease severity, and reduced inflammatory cytokine levels in acute ischemic stroke patients. Neurol Sci. 2018;39(10):1757–65.CrossRef
12.
go back to reference Moghaddam AS, Afshari JT, Esmaeili SA, Saburi E, Joneidi Z, Momtazi-Borojeni AA. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis. 2019;285:1–9.CrossRef Moghaddam AS, Afshari JT, Esmaeili SA, Saburi E, Joneidi Z, Momtazi-Borojeni AA. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis. 2019;285:1–9.CrossRef
13.
go back to reference Ma Y, Ma M, Sun J, Li W, Li Y, Guo X, et al. CHIR-99021 regulates mitochondrial remodelling via beta-catenin signalling and miRNA expression during endodermal differentiation. J Cell Sci. 2019;132(15):jcs229948.CrossRef Ma Y, Ma M, Sun J, Li W, Li Y, Guo X, et al. CHIR-99021 regulates mitochondrial remodelling via beta-catenin signalling and miRNA expression during endodermal differentiation. J Cell Sci. 2019;132(15):jcs229948.CrossRef
14.
go back to reference Sherif IO, Al-Shaalan NH. Vildagliptin attenuates hepatic ischemia/reperfusion injury via the TLR4/NF-kappaB signaling pathway. Oxidative Med Cell Longev. 2018;2018:3509091.CrossRef Sherif IO, Al-Shaalan NH. Vildagliptin attenuates hepatic ischemia/reperfusion injury via the TLR4/NF-kappaB signaling pathway. Oxidative Med Cell Longev. 2018;2018:3509091.CrossRef
16.
go back to reference Zhang W, Zhang Y, Ding K, Zhang H, Zhao Q, Liu Z, Xu Y. Involvement of JNK1/2-NF-kappaBp65 in the regulation of HMGB2 in myocardial ischemia/reperfusion-induced apoptosis in human AC16 cardiomyocytes. Biomed Pharmacother. 2018;106:1063–71.CrossRef Zhang W, Zhang Y, Ding K, Zhang H, Zhao Q, Liu Z, Xu Y. Involvement of JNK1/2-NF-kappaBp65 in the regulation of HMGB2 in myocardial ischemia/reperfusion-induced apoptosis in human AC16 cardiomyocytes. Biomed Pharmacother. 2018;106:1063–71.CrossRef
17.
go back to reference Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, Savitsky D, Ronfani L, Akira S, Bianchi ME, Honda K, Tamura T, Kodama T, Taniguchi T. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 2009;462(7269):99–103.CrossRef Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, Savitsky D, Ronfani L, Akira S, Bianchi ME, Honda K, Tamura T, Kodama T, Taniguchi T. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 2009;462(7269):99–103.CrossRef
19.
go back to reference Zhang WY, Zhang QL, Xu MJ. Effects of propofol on myocardial ischemia reperfusion injury through inhibiting the JAK/STAT pathway. Eur Rev Med Pharmacol Sci. 2019;23(14):6339–45.PubMed Zhang WY, Zhang QL, Xu MJ. Effects of propofol on myocardial ischemia reperfusion injury through inhibiting the JAK/STAT pathway. Eur Rev Med Pharmacol Sci. 2019;23(14):6339–45.PubMed
20.
go back to reference Wang Y, Qi X, Wang C, Zhao D, Wang H, Zhang J. Effects of propofol on myocardial ischemia-reperfusion injury in rats with type-2 diabetes mellitus. Biomed Rep. 2017;6(1):69–74.CrossRef Wang Y, Qi X, Wang C, Zhao D, Wang H, Zhang J. Effects of propofol on myocardial ischemia-reperfusion injury in rats with type-2 diabetes mellitus. Biomed Rep. 2017;6(1):69–74.CrossRef
21.
go back to reference Mushtaque RS, Hameed S, Mushtaque R, Idrees M, Siraj F. Role of cardio-specific micro-ribonucleic acids and correlation with cardiac biomarkers in acute coronary syndrome: a comprehensive systematic review. Cureus. 2019;11(10):e5878.PubMedPubMedCentral Mushtaque RS, Hameed S, Mushtaque R, Idrees M, Siraj F. Role of cardio-specific micro-ribonucleic acids and correlation with cardiac biomarkers in acute coronary syndrome: a comprehensive systematic review. Cureus. 2019;11(10):e5878.PubMedPubMedCentral
22.
go back to reference Shen S, Zhou J, Meng S, Wu J, Ma J, Zhu C, et al. The protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax. Exp Ther Med. 2017;14(5):4077–82.PubMedPubMedCentral Shen S, Zhou J, Meng S, Wu J, Ma J, Zhu C, et al. The protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax. Exp Ther Med. 2017;14(5):4077–82.PubMedPubMedCentral
23.
go back to reference Signorelli SS, Volsi GL, Pitruzzella A, Fiore V, Mangiafico M, Vanella L, et al. Circulating miR-130a, miR-27b, and miR-210 in patients with peripheral artery disease and their potential relationship with oxidative stress. Angiology. 2016;67(10):945–50.CrossRef Signorelli SS, Volsi GL, Pitruzzella A, Fiore V, Mangiafico M, Vanella L, et al. Circulating miR-130a, miR-27b, and miR-210 in patients with peripheral artery disease and their potential relationship with oxidative stress. Angiology. 2016;67(10):945–50.CrossRef
24.
go back to reference Giuliani A, Prattichizzo F, Micolucci L, Ceriello A, Procopio AD, Rippo MR. Mitochondrial (Dys) function in inflammaging: do MitomiRs influence the energetic, oxidative, and inflammatory status of senescent cells? Mediat Inflamm. 2017;2017:2309034.CrossRef Giuliani A, Prattichizzo F, Micolucci L, Ceriello A, Procopio AD, Rippo MR. Mitochondrial (Dys) function in inflammaging: do MitomiRs influence the energetic, oxidative, and inflammatory status of senescent cells? Mediat Inflamm. 2017;2017:2309034.CrossRef
25.
go back to reference Tang C, Yang Z, Chen D, Xie Q, Peng T, Wu J, Qi S. Downregulation of miR-130a promotes cell growth and epithelial to mesenchymal transition by activating HMGB2 in glioma. Int J Biochem Cell Biol. 2017;93:25–31.CrossRef Tang C, Yang Z, Chen D, Xie Q, Peng T, Wu J, Qi S. Downregulation of miR-130a promotes cell growth and epithelial to mesenchymal transition by activating HMGB2 in glioma. Int J Biochem Cell Biol. 2017;93:25–31.CrossRef
26.
go back to reference Xu CH, Xiao LM, Liu Y, Chen LK, Zheng SY, Zeng EM, et al. The lncRNA HOXA11-AS promotes glioma cell growth and metastasis by targeting miR-130a-5p/HMGB2. Eur Rev Med Pharmacol Sci. 2019;23(1):241–52.PubMed Xu CH, Xiao LM, Liu Y, Chen LK, Zheng SY, Zeng EM, et al. The lncRNA HOXA11-AS promotes glioma cell growth and metastasis by targeting miR-130a-5p/HMGB2. Eur Rev Med Pharmacol Sci. 2019;23(1):241–52.PubMed
27.
go back to reference Zhang W, Zhang Y, Ding K, Zhang H, Zhao Q, Liu Z, et al. Involvement of JNK1/2-NF-kappaBp65 in the regulation of HMGB2 in myocardial ischemia/reperfusion-induced apoptosis in human AC16 cardiomyocytes. Biomed Pharmacother. 2018;106:1063–71.CrossRef Zhang W, Zhang Y, Ding K, Zhang H, Zhao Q, Liu Z, et al. Involvement of JNK1/2-NF-kappaBp65 in the regulation of HMGB2 in myocardial ischemia/reperfusion-induced apoptosis in human AC16 cardiomyocytes. Biomed Pharmacother. 2018;106:1063–71.CrossRef
28.
go back to reference Liu ZH, Dai DP, Ding FH, Pan WQ, Fang YH, Zhang Q, et al. Association of serum HMGB2 level with MACE at 1 mo of myocardial infarction: aggravation of myocardial ischemic injury in rats by HMGB2 via ROS. Am J Physiol Heart Circ Physiol. 2017;312(3):H422–36.CrossRef Liu ZH, Dai DP, Ding FH, Pan WQ, Fang YH, Zhang Q, et al. Association of serum HMGB2 level with MACE at 1 mo of myocardial infarction: aggravation of myocardial ischemic injury in rats by HMGB2 via ROS. Am J Physiol Heart Circ Physiol. 2017;312(3):H422–36.CrossRef
29.
go back to reference Tan XH, Zheng XM, Yu LX, He J, Zhu HM, Ge XP, et al. Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling. J Cell Mol Med. 2017;21(11):2909–25.CrossRef Tan XH, Zheng XM, Yu LX, He J, Zhu HM, Ge XP, et al. Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling. J Cell Mol Med. 2017;21(11):2909–25.CrossRef
30.
go back to reference Kocaturk H, Bedir F, Altay MS, Bakan E, Suleyman B, Yazici GN, Sunar M, Suleyman Z, Suleyman H. The effect of desloratadine on ischemia reperfusion induced oxidative and inflammatory renal injury in rats. Ren Fail. 2020;42(1):531–8.CrossRef Kocaturk H, Bedir F, Altay MS, Bakan E, Suleyman B, Yazici GN, Sunar M, Suleyman Z, Suleyman H. The effect of desloratadine on ischemia reperfusion induced oxidative and inflammatory renal injury in rats. Ren Fail. 2020;42(1):531–8.CrossRef
31.
go back to reference Zhang W, Liu X, Jiang Y, Wang N, Li F, Xin H. 6-Gingerol attenuates ischemia-reperfusion-induced cell apoptosis in human AC16 cardiomyocytes through HMGB2-JNK1/2-NF-kappaB pathway. Evid Based Complement Alternat Med. 2019;2019:8798653.PubMedPubMedCentral Zhang W, Liu X, Jiang Y, Wang N, Li F, Xin H. 6-Gingerol attenuates ischemia-reperfusion-induced cell apoptosis in human AC16 cardiomyocytes through HMGB2-JNK1/2-NF-kappaB pathway. Evid Based Complement Alternat Med. 2019;2019:8798653.PubMedPubMedCentral
32.
go back to reference He HY, Ren L, Guo T, Deng YH. Neuronal autophagy aggravates microglial inflammatory injury by downregulating CX3CL1/fractalkine after ischemic stroke. Neural Regen Res. 2019;14(2):280–8.CrossRef He HY, Ren L, Guo T, Deng YH. Neuronal autophagy aggravates microglial inflammatory injury by downregulating CX3CL1/fractalkine after ischemic stroke. Neural Regen Res. 2019;14(2):280–8.CrossRef
33.
go back to reference Lopes AP, van Roon JAG, Blokland SLM, Wang M, Chouri E, Hartgring SAY, et al. MicroRNA-130a contributes to type-2 classical DC-activation in Sjogren’s syndrome by targeting mitogen- and stress-activated protein kinase-1. Front Immunol. 2019;10:1335.CrossRef Lopes AP, van Roon JAG, Blokland SLM, Wang M, Chouri E, Hartgring SAY, et al. MicroRNA-130a contributes to type-2 classical DC-activation in Sjogren’s syndrome by targeting mitogen- and stress-activated protein kinase-1. Front Immunol. 2019;10:1335.CrossRef
Metadata
Title
microRNA-130a-5p suppresses myocardial ischemia reperfusion injury by downregulating the HMGB2/NF-κB axis
Authors
Yong Li
Hongbo Zhang
Zhanhu Li
Xiaoju Yan
Yuan Li
Shuai Liu
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2021
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-020-01742-4

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