Skip to main content
Log in

RBM3 interacts with Raptor to regulate autophagy and protect cardiomyocytes from ischemia–reperfusion-induced injury

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Acute myocardial infarction (AMI) is a common disease with high morbidity and mortality worldwide. However, postinfarction pathogenesis remains unclear, and it is particularly important to identify new therapeutic targets. The RNA-binding motif protein RBM3 (also known as cold-inducible protein) is known to promote translation and is associated with tumor proliferation and neuroprotection. However, little is known about the biological effects of RBM3 on myocardial infarction. In the present study, we found that RBM3 expression was significantly upregulated in ischemia–reperfusion (I/R) condition and downregulation of RBM3 inhibited autophagy and promoted apoptosis in cardiomyocytes. We confirmed that RBM3 interacts with Raptor to regulate the autophagy pathway. Taken together, these findings illustrate the protective effects of RBM3 against I/R-induced myocardial apoptosis through the autophagy pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Chen G, Xu C, Gillette TG, Huang T, Huang P, Li Q et al (2020) Cardiomyocyte-derived small extracellular vesicles can signal eNOS activation in cardiac microvascular endothelial cells to protect against ischemia/reperfusion injury. Theranostics 10(25):11754–11774. https://doi.org/10.7150/thno.43163

    Article  CAS  Google Scholar 

  2. Chip S, Zelmer A, Ogunshola O, Felderhoff-Mueser U, Nitsch C, Bührer C et al (2011) The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. Neurobiol Dis 43(2):388–396. https://doi.org/10.1016/j.nbd.2011.04.010

    Article  CAS  Google Scholar 

  3. Doherty J, Baehrecke EH (2018) Life, death and autophagy. Nat Cell Biol 20(10):1110–1117. https://doi.org/10.1038/s41556-018-0201-5

    Article  CAS  Google Scholar 

  4. Fuentes E, Moore-Carrasco R, de Andrade Paes AM, Trostchansky A (2019) Role of platelet activation and oxidative stress in the evolution of myocardial infarction. J Cardiovasc Pharmacol Ther 24(6):509–520. https://doi.org/10.1177/1074248419861437

    Article  CAS  Google Scholar 

  5. Fuentes-Fayos AC, Vazquez-Borrego MC, Jimenez-Vacas JM, Bejarano L, Pedraza-Arevalo S, F LL, et al (2020) Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3. Brain J Neuro 143(11):3273–93. https://doi.org/10.1093/brain/awaa273

    Article  Google Scholar 

  6. Ganner A, Gehrke C, Klein M, Thegtmeier L, Matulenski T, Wingendorf L et al (2021) VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma. Sci Rep 11(1):14827. https://doi.org/10.1038/s41598-021-94132-5

    Article  CAS  Google Scholar 

  7. Gong Y, Yang J, Cai J, Liu Q, Zhang J, ZhangZJJocp. (2019) Effect of Gpx3 gene silencing by siRNA on apoptosis and autophagy in chicken cardiomyocytes. J Cell Physiol 234(6):7828–38. https://doi.org/10.1002/jcp.27842

    Article  CAS  Google Scholar 

  8. Hamacher-Brady A, Brady NR, Gottlieb RA (2006) The interplay between pro-death and pro-survival signaling pathways in myocardial ischemia/reperfusion injury: apoptosis meets autophagy. Cardiovasc Drugs Ther 20(6):445–462. https://doi.org/10.1007/s10557-006-0583-7

    Article  CAS  Google Scholar 

  9. Heusch G (2020) Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 17(12):773–789. https://doi.org/10.1038/s41569-020-0403-y

    Article  Google Scholar 

  10. Jackson TC, Janesko-Feldman K, Carlson SW, Kotermanski SE, Kochanek PM (2019) Robust RBM3 and beta-klotho expression in developing neurons in the human brain. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 39(12):2355–2367. https://doi.org/10.1177/0271678X19878889

    Article  CAS  Google Scholar 

  11. Ma S, Wang Y, Chen Y, Cao F (2015) The role of the autophagy in myocardial ischemia/reperfusion injury. Biochem Biophys Acta 1852(2):271–276. https://doi.org/10.1016/j.bbadis.2014.05.010

    Article  CAS  Google Scholar 

  12. Ma R, Zhao LN, Yang H, Wang YF, Hu J, Zang J et al (2018) RNA binding motif protein 3 (RBM3) drives radioresistance in nasopharyngeal carcinoma by reducing apoptosis via the PI3K/AKT/Bcl-2 signaling pathway. Am J Transl Res 10(12):4130–4140

    CAS  Google Scholar 

  13. Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A et al (2013) Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med 19(11):1478–1488. https://doi.org/10.1038/nm.3322

    Article  CAS  Google Scholar 

  14. Mo Y, Tang L, Ma Y, Wu S (2016) Pramipexole pretreatment attenuates myocardial ischemia/reperfusion injury through upregulation of autophagy. Biochem Biophys Res Commun 473(4):1119–1124. https://doi.org/10.1016/j.bbrc.2016.04.026

    Article  CAS  Google Scholar 

  15. Ong SB, Hernandez-Resendiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA et al (2018) Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther 186:73–87. https://doi.org/10.1016/j.pharmthera.2018.01.001

    Article  CAS  Google Scholar 

  16. Peretti D, Bastide A, Radford H, Verity N, Molloy C, Martin MG et al (2015) RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature 518(7538):236–239. https://doi.org/10.1038/nature14142

    Article  CAS  Google Scholar 

  17. Poss J, Koster J, Fuernau G, Eitel I, de Waha S, Ouarrak T et al (2017) Risk stratification for patients in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 69(15):1913–1920. https://doi.org/10.1016/j.jacc.2017.02.027

    Article  Google Scholar 

  18. Reichert K, Colantuono B, McCormack I, Rodrigues F, Pavlov V, Abid MR. 2017 Murine left anterior descending (LAD) coronary artery ligation: an improved and simplified model for myocardial infarction. J Vis Exp (122). https://doi.org/10.3791/55353.

  19. Riquelme JA, Chavez MN, Mondaca-Ruff D, Bustamante M, Vicencio JM, Quest AF et al (2016) Therapeutic targeting of autophagy in myocardial infarction and heart failure. Expert Rev Cardiovasc Ther 14(9):1007–1019. https://doi.org/10.1080/14779072.2016.1202760

    Article  CAS  Google Scholar 

  20. Sakurai T, Kashida H, Komeda Y, Nagai T, Hagiwara S, Watanabe T et al (2017) Stress response protein RBM3 promotes the development of colitis-associated cancer. Inflamm Bowel Dis 23(1):57–65. https://doi.org/10.1097/MIB.0000000000000968

    Article  Google Scholar 

  21. Saparov A, Ogay V, Nurgozhin T, Chen WCW, Mansurov N, Issabekova A, Zhakupova J (2017) Role of the immune system in cardiac tissue damage and repair following myocardial infarction. Inflamm Res 66:739–751

    Article  CAS  Google Scholar 

  22. Si W, Li Z, Huang Z, Ye S, Li X, Li Y et al (2020) RNA binding protein motif 3 inhibits oxygen-glucose deprivation/reoxygenation-induced apoptosis through promoting stress granules formation in PC12 cells and rat primary cortical neurons. Front Cell Neurosci 14:559384. https://doi.org/10.3389/fncel.2020.559384

    Article  CAS  Google Scholar 

  23. Song S, Tan J, Miao Y, Li M, Zhang QJJocp. (2017) Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress. J Cell Physiol 232(11):2977–84. https://doi.org/10.1002/jcp.25785

    Article  CAS  Google Scholar 

  24. Tong G, von Garlen NNA, Wowro SJ, Lam PD, Krech J, Berger F et al (2019) Post-TTM rebound pyrexia after ischemia-reperfusion injury results in sterile inflammation and apoptosis in cardiomyocytes. Mediators Inflamm 2019:6431957. https://doi.org/10.1155/2019/6431957

    Article  CAS  Google Scholar 

  25. Wang ZG, Li H, Huang Y, Li R, Wang XF, Yu LX et al (2017) Nerve growth factor-induced Akt/mTOR activation protects the ischemic heart via restoring autophagic flux and attenuating ubiquitinated protein accumulation. Oncotarget 8(3):5400–13. https://doi.org/10.18632/oncotarget.14284

    Article  Google Scholar 

  26. Wang M, Wang RY, Zhou JH, Xie XH, Sun GB, Sun XB (2020) Calenduloside E Ameliorates myocardial ischemia-reperfusion injury through regulation of AMPK and mitochondrial OPA1. Oxid Med Cell Longev 2020:2415269. https://doi.org/10.1155/2020/2415269

    Article  CAS  Google Scholar 

  27. Xie CM, Tan M, Lin XT, Wu D, Jiang Y, Tan Y et al (2019) The FBXW7-SHOC2-Raptor axis controls the cross-talks between the RAS-ERK and mTORC1 signaling pathways. Cell reports 26(11):3037–50 e4. https://doi.org/10.1016/j.celrep.2019.02.052

    Article  CAS  Google Scholar 

  28. Yan L, Guo N, Cao Y, Zeng S, Wang J, Lv F et al (2018) miRNA-145 inhibits myocardial infarction-induced apoptosis through autophagy via Akt3/mTOR signaling pathway in vitro and in vivo. Int J Mol Med 42(3):1537–1547. https://doi.org/10.3892/ijmm.2018.3748

    Article  CAS  Google Scholar 

  29. Yang HJ, Ju F, Guo XX, Ma SP, Wang L, Cheng BF et al (2017) RNA-binding protein RBM3 prevents NO-induced apoptosis in human neuroblastoma cells by modulating p38 signaling and miR-143. Sci Rep 7:41738. https://doi.org/10.1038/srep41738

    Article  CAS  Google Scholar 

  30. Yang HJ, Zhuang RJ, Li YB, Li T, Yuan X, Lei BB et al (2019) Cold-inducible protein RBM3 mediates hypothermic neuroprotection against neurotoxin rotenone via inhibition on MAPK signalling. J Cell Mol Med 23(10):7010–7020. https://doi.org/10.1111/jcmm.14588

    Article  CAS  Google Scholar 

  31. Yuan X, Zhang J, Ma TT, Zhuang RJ, Lei BB, Wang L et al (2021) Expression regulation of cold-inducible protein RBM3 by FAK/Src signaling for neuroprotection against rotenone under mild hypothermia. Biochem Biophys Res Commun 534:240–247. https://doi.org/10.1016/j.bbrc.2020.11.105

    Article  CAS  Google Scholar 

  32. Zech ATL, Singh SR, Schlossarek S, Carrier L (2019) Autophagy in cardiomyopathies. Biochim Biophys Acta Mol Cell Res. https://doi.org/10.1016/j.bbamcr.2019.01.013

    Article  Google Scholar 

  33. Zhang L, Liang W, Li Y, Yan J, Xue J, Guo Q et al (2021) Mild therapeutic hypothermia improves neurological outcomes in a rat model of cardiac arrest. Brain Res Bull 173:97–107. https://doi.org/10.1016/j.brainresbull.2021.05.014

    Article  CAS  Google Scholar 

  34. Zhang J, Chai W, Xiang Z, Zhou X, Zhang P (2021) MZF1 alleviates oxidative stress and apoptosis induced by rotenone in SH-SY5Y cells by promoting RBM3 transcription. J Toxicol Sci 46(10):477–486. https://doi.org/10.2131/jts.46.477

    Article  CAS  Google Scholar 

  35. Zhu X, Buhrer C, Wellmann S (2016) Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold. Cellular and molecular life sciences : CMLS 73(20):3839–3859. https://doi.org/10.1007/s00018-016-2253-7

    Article  CAS  Google Scholar 

  36. Zhu X, Yan J, Bregere C, Zelmer A, Goerne T, Kapfhammer JP et al (2019) RBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury. Nat Commun 10(1):3983. https://doi.org/10.1038/s41467-019-11870-x

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported in part by the National Science Foundation of China (grant nos. 31760292 and 81460210), the Department project of Science and Technology of Yunnan Province (grant nos. 2017FA035 and 2019ZF011-2), Joint Fund for Basic Research of Yunnan Provincial Department of Science and Technology and Kunming Medical University (grant no. 202101AY070001-079), Kunming Science and Technology Plan Project (grant no. 2019–1-N-25318000003496), and the Department project of Education of Yunnan Province (grant no. 2020Y0119).

Author information

Authors and Affiliations

Authors

Contributions

DL and LS conceived and designed the study; LMTW, CYL, PR, and XW performed the experiments; YZX and LY analyzed the data; DL, LS, and NW wrote the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Lin Sun or Di Lu.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

• RBM3 expression is up-regulated under myocardial ischemia–reperfusion conditions.

• RBM3 regulates apoptosis and autophagy in cardiomyocytes.

• RBM3 may interact with Raptor to regulate cardiomyocyte autophagy.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, N., Wang, L., Li, C. et al. RBM3 interacts with Raptor to regulate autophagy and protect cardiomyocytes from ischemia–reperfusion-induced injury. J Physiol Biochem 79, 47–57 (2023). https://doi.org/10.1007/s13105-022-00919-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-022-00919-z

Keywords

Navigation