MiR-926-3p Influences Myocardial Injury in Septic Mice Through Regulation of MTOR Signaling Pathway by Targeting TSC1

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2023 May 12

PMID 37171398

Authors

Feng Yan

Qian Wang

Huiyu Yang

Hui Lv

Weiwei Qin

Affiliations

Soon will be listed here.

Abstract

Background: The purpose of this study is to investigate the influence of miR-926-3p on myocardial injury and its mechanisms.

Methods: An animal model of sepsis was constructed by CLP, and animals were randomly divided into 4 groups: C group, miR-926-3p inhibitor group, CLP + NC group, and CLP + miR-926-3p inhibitor group.

Results: Compared with those in C group, echocardiographic parameters remarkably declined in CLP + NC group. Compared with CLP + NC group, miR-926-3p inhibitor group indicated elevated echocardiographic parameters in mice, pathological improvement tendency of myocardial tissues and distinct reduction in cardiomyocyte apoptosis. It could be observed by electron microscopy that the number of lysosomes in miR-926-3p inhibitor group was greatly increased relative to CLP + NC group. Immunofluorescence exhibited that the number of green fluorescent puncta was significantly higher in miR-926-3p inhibitor group as compared to that in CLP + NC group. The autophagic flow was verified by observing the relative expression of LC3II at different times. The results of Western blotting manifested that miR-926-3p inhibitor up-regulated mTOR-related protein expressions and down-regulated the protein expression of p-mTOR. LPS was adopted to induce cardiomyocyte injury , and the results confirmed that, identical to experiments, miR-926-3p inhibitor was able to up-regulate the protein expressions of mTOR-related protein and down-regulate p-mTOR protein expression in cardiomyocytes. After addition of MHY1485, The expression of mTOR-related proteins changes in each group.

Conclusion: Inhibition of miR-926-3p enhances autophagy through regulation of the mTOR signaling pathway, thus ameliorating myocardial injury in septic mice.

References

Xie M, Morales C, Lavandero S, Hill J . Tuning flux: autophagy as a target of heart disease therapy. Curr Opin Cardiol. 2011; 26(3):216-22. PMC: 3607640. DOI: 10.1097/HCO.0b013e328345980a. View

Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-10. PMC: 4968574. DOI: 10.1001/jama.2016.0287. View

Chen J, Wang B, Lai J, Braunstein Z, He M, Ruan G . Trimetazidine Attenuates Cardiac Dysfunction in Endotoxemia and Sepsis by Promoting Neutrophil Migration. Front Immunol. 2018; 9:2015. PMC: 6131494. DOI: 10.3389/fimmu.2018.02015. View

Wang X, Yu Y . MiR-146b protect against sepsis induced mice myocardial injury through inhibition of Notch1. J Mol Histol. 2018; 49(4):411-417. DOI: 10.1007/s10735-018-9781-4. View

Mizushima N . Autophagy: process and function. Genes Dev. 2007; 21(22):2861-73. DOI: 10.1101/gad.1599207. View

Mizushima N, Levine B . Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010; 12(9):823-30. PMC: 3127249. DOI: 10.1038/ncb0910-823. View

Shintani T, Klionsky D . Autophagy in health and disease: a double-edged sword. Science. 2004; 306(5698):990-5. PMC: 1705980. DOI: 10.1126/science.1099993. View

Hunter J, Doddi M . Sepsis and the heart. Br J Anaesth. 2009; 104(1):3-11. DOI: 10.1093/bja/aep339. View

Maloney P . Sepsis and septic shock. Emerg Med Clin North Am. 2013; 31(3):583-600. DOI: 10.1016/j.emc.2013.04.006. View

10.

Mofarrahi M, Sigala I, Guo Y, Godin R, Davis E, Petrof B . Autophagy and skeletal muscles in sepsis. PLoS One. 2012; 7(10):e47265. PMC: 3467208. DOI: 10.1371/journal.pone.0047265. View

11.

Li J, Li G, Jing X, Li Y, Ye Q, Jia H . Assessment of clinical sepsis-associated biomarkers in a septic mouse model. J Int Med Res. 2018; 46(6):2410-2422. PMC: 6023044. DOI: 10.1177/0300060518764717. View

12.

Ehrman R, Sullivan A, Favot M, Sherwin R, Reynolds C, Abidov A . Pathophysiology, echocardiographic evaluation, biomarker findings, and prognostic implications of septic cardiomyopathy: a review of the literature. Crit Care. 2018; 22(1):112. PMC: 5934857. DOI: 10.1186/s13054-018-2043-8. View

13.

Essandoh K, Li Y, Huo J, Fan G . MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response. Shock. 2016; 46(2):122-31. PMC: 4949115. DOI: 10.1097/SHK.0000000000000604. View

14.

Fattahi F, Ward P . Complement and sepsis-induced heart dysfunction. Mol Immunol. 2016; 84:57-64. PMC: 5366269. DOI: 10.1016/j.molimm.2016.11.012. View

15.

Lee S, Lee S, Coronata A, Fredenburgh L, Chung S, Perrella M . Carbon monoxide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis. Antioxid Redox Signal. 2013; 20(3):432-42. PMC: 3894711. DOI: 10.1089/ars.2013.5368. View

16.

Angus D, Pereira C, Silva E . Epidemiology of severe sepsis around the world. Endocr Metab Immune Disord Drug Targets. 2006; 6(2):207-12. DOI: 10.2174/187153006777442332. View

17.

Venkataraman R, Subramanian S, Kellum J . Clinical review: extracorporeal blood purification in severe sepsis. Crit Care. 2003; 7(2):139-45. PMC: 270630. DOI: 10.1186/cc1889. View

18.

Inoki K, Li Y, Xu T, Guan K . Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003; 17(15):1829-34. PMC: 196227. DOI: 10.1101/gad.1110003. View

19.

Kim Y, Guan K . mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015; 125(1):25-32. PMC: 4382265. DOI: 10.1172/JCI73939. View

20.

Rello J, Valenzuela-Sanchez F, Ruiz-Rodriguez M, Moyano S . Sepsis: A Review of Advances in Management. Adv Ther. 2017; 34(11):2393-2411. PMC: 5702377. DOI: 10.1007/s12325-017-0622-8. View