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Thorac Cardiovasc Surg
DOI: 10.1055/s-0044-1787691
Original Basic Science

DEX Inhibits H/R-induced Cardiomyocyte Ferroptosis by the miR-141-3p/lncRNA TUG1 Axis

Mei Zhu 
1   Department of Anesthesiology, Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou, People's Republic of China
,
Zhiguo Yuan
1   Department of Anesthesiology, Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou, People's Republic of China
,
Chuanyun Wen
1   Department of Anesthesiology, Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou, People's Republic of China
,
Xiaojia Wei
1   Department of Anesthesiology, Taizhou People's Hospital Affiliated to Nanjing Medical University, Taizhou, People's Republic of China
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Abstract

Background Ferroptosis is emerging as a critical pathway in ischemia/reperfusion (I/R) injury, contributing to compromised cardiac function and predisposing individuals to sepsis and myocardial failure. The study investigates the underlying mechanism of dexmedetomidine (DEX) in hypoxia/reoxygenation (H/R)-induced ferroptosis in cardiomyocytes, aiming to identify novel targets for myocardial I/R injury treatment.

Methods H9C2 cells were subjected to H/R and treated with varying concentrations of DEX. Additionally, H9C2 cells were transfected with miR-141-3p inhibitor followed by H/R treatment. Levels of miR-141-3p, long noncoding RNA (lncRNA) taurine upregulated 1 (TUG1), Fe2+, glutathione (GSH), and malondialdehyde were assessed. Reactive oxygen species (ROS) generation was measured via fluorescent labeling. Expression of ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) was determined using Western blot. The interaction between miR-141-3p and lncRNA TUG1 was evaluated through RNA pull-down assay and dual-luciferase reporter gene assays. The stability of lncRNA TUG1 was assessed using actinomycin D.

Results DEX ameliorated H/R-induced cardiomyocyte injury and elevated miR-141-3p expression in cardiomyocytes. DEX treatment increased cell viability, Fe2+, and ROS levels while decreasing ACSL4 protein expression. Furthermore, DEX upregulated GSH and GPX4 protein levels. miR-141-3p targeted lncRNA TUG1, reducing its stability and overall expression. Inhibition of miR-141-3p or overexpression of lncRNA TUG1 partially reversed the inhibitory effect of DEX on H/R-induced ferroptosis in cardiomyocytes.

Conclusion DEX mitigated H/R-induced ferroptosis in cardiomyocytes by upregulating miR-141-3p expression and downregulating lncRNA TUG1 expression, unveiling a potential therapeutic strategy for myocardial I/R injury.

Keywords

dexmedetomidine - ischemia/reperfusion - myocardial - ferroptosis - miR-141-3p

Authors' Contribution

M. Z.: Guarantor of the integrity of the entire study, contributed to study concepts, study design, data analysis, statistical analysis, manuscript editing, and manuscript review.


Z. Y.: Contributed to the definition of intellectual content and manuscript preparation.


C. W.: Conducted literature research and experimental studies.


X. W.: Contributed to data acquisition.




Publication History

Received: 21 March 2024

Accepted: 17 May 2024

Article published online:
18 June 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Algoet M, Janssens S, Himmelreich U. et al. Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends Cardiovasc Med 2023; 33 (06) 357-366
    CrossrefPubMedGoogle Scholar
  • 2 Wu MY, Yiang GT, Liao WT. et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem 2018; 46 (04) 1650-1667
    CrossrefPubMedGoogle Scholar
  • 3 Sun M, Wang R, Xia R, Xia Z, Wu Z, Wang T. Amelioration of myocardial ischemia/reperfusion injury in diabetes: a narrative review of the mechanisms and clinical applications of dexmedetomidine. Front Pharmacol 2022; 13: 949754
    CrossrefPubMedGoogle Scholar
  • 4 Chen Y, Fan H, Wang S, Tang G, Zhai C, Shen L. Ferroptosis: a novel therapeutic target for ischemia-reperfusion injury. Front Cell Dev Biol 2021; 9: 688605
    CrossrefPubMedGoogle Scholar
  • 5 Fang X, Ardehali H, Min J, Wang F. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol 2023; 20 (01) 7-23
    CrossrefPubMedGoogle Scholar
  • 6 Wang X, Zhou H, Cheng R. et al. Role of miR-326 in neonatal hypoxic-ischemic brain damage pathogenesis through targeting of the δ-opioid receptor. Mol Brain 2020; 13 (01) 51
    CrossrefPubMedGoogle Scholar
  • 7 Qiu L, Ge L, Hu Q. Dexmedetomidine protects SK-N-SH nerve cells from oxidative injury by maintaining iron homeostasis. Biol Pharm Bull 2020; 43 (03) 424-431
    CrossrefPubMedGoogle Scholar
  • 8 Ho PTB, Clark IM, Le LTT. MicroRNA-based diagnosis and therapy. Int J Mol Sci 2022; 23 (13) 7167
    CrossrefPubMedGoogle Scholar
  • 9 Ghafouri-Fard S, Shoorei H, Taheri M. Non-coding RNAs participate in the ischemia-reperfusion injury. Biomed Pharmacother 2020; 129: 110419
    CrossrefPubMedGoogle Scholar
  • 10 Liu M, Yang P, Fu D. et al. Allicin protects against myocardial I/R by accelerating angiogenesis via the miR-19a-3p/PI3K/AKT axis. Aging (Albany NY) 2021; 13 (19) 22843-22855
    CrossrefPubMedGoogle Scholar
  • 11 Zhao J, Li X, Hu J. et al. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res 2019; 115 (07) 1205-1216
    CrossrefPubMedGoogle Scholar
  • 12 Zhang L, Dan Y, Ou C. et al. Identification and validation of novel biomarker TRIM8 related to cervical cancer. Front Oncol 2022; 12: 1002040
    CrossrefPubMedGoogle Scholar
  • 13 Li T, Chen Q, Dai J. et al. MicroRNA-141-3p attenuates oxidative stress-induced hepatic ischemia reperfusion injury via Keap1/Nrf2 pathway. Mol Biol Rep 2022; 49 (08) 7575-7585
    CrossrefPubMedGoogle Scholar
  • 14 Yao B, Wan X, Zheng X. et al. Critical roles of microRNA-141-3p and CHD8 in hypoxia/reoxygenation-induced cardiomyocyte apoptosis. Cell Biosci 2020; 10: 20
    CrossrefPubMedGoogle Scholar
  • 15 Dykes IM, Emanueli C. Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genomics Proteomics Bioinformatics 2017; 15 (03) 177-186
    CrossrefPubMedGoogle Scholar
  • 16 Marinescu MC, Lazar AL, Marta MM, Cozma A, Catana CS. Non-coding RNAs: prevention, diagnosis, and treatment in myocardial ischemia-reperfusion injury. Int J Mol Sci 2022; 23 (05) 2728
    CrossrefPubMedGoogle Scholar
  • 17 Guo C, Qi Y, Qu J, Gai L, Shi Y, Yuan C. Pathophysiological Functions of the lncRNA TUG1. Curr Pharm Des 2020; 26 (06) 688-700
    CrossrefPubMedGoogle Scholar
  • 18 Zhang Y, Tao Y, Liao Q. Long noncoding RNA: a crosslink in biological regulatory network. Brief Bioinform 2018; 19 (05) 930-945
    CrossrefPubMedGoogle Scholar
  • 19 Ong SB, Katwadi K, Kwek XY. et al. Non-coding RNAs as therapeutic targets for preventing myocardial ischemia-reperfusion injury. Expert Opin Ther Targets 2018; 22 (03) 247-261
    CrossrefPubMedGoogle Scholar
  • 20 Wu X, Liu Y, Mo S, Wei W, Ye Z, Su Q. LncRNA TUG1 competitively binds to miR-340 to accelerate myocardial ischemia-reperfusion injury. FASEB J 2021; 35 (01) e21163
    PubMedGoogle Scholar
  • 21 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25 (04) 402-408
    CrossrefPubMedGoogle Scholar
  • 22 Zhang X, Xue C, Cui X. et al. Circ_0075829 facilitates the progression of pancreatic carcinoma by sponging miR-1287–5p and activating LAMTOR3 signalling. J Cell Mol Med 2020; 24 (24) 14596-14607
    CrossrefPubMedGoogle Scholar
  • 23 Fu D, Gao T, Liu M. et al. LncRNA TUG1 aggravates cardiomyocyte apoptosis and myocardial ischemia/reperfusion injury. Histol Histopathol 2021; 36 (12) 1261-1272
    PubMedGoogle Scholar
  • 24 Pan Y, Wang X, Liu X, Shen L, Chen Q, Shu Q. Targeting ferroptosis as a promising therapeutic strategy for ischemia-reperfusion injury. Antioxidants 2022; 11 (11) 2196
    CrossrefPubMedGoogle Scholar
  • 25 Deng L, He S, Guo N, Tian W, Zhang W, Luo L. Molecular mechanisms of ferroptosis and relevance to inflammation. Inflamm Res 2023; 72 (02) 281-299
    CrossrefPubMedGoogle Scholar
  • 26 Li X, Ma N, Xu J. et al. Targeting ferroptosis: pathological mechanism and treatment of ischemia-reperfusion injury. Oxid Med Cell Longev 2021; 2021: 1587922
    CrossrefPubMedGoogle Scholar
  • 27 Cai Y, Xu H, Yan J, Zhang L, Lu Y. Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep 2014; 9 (05) 1542-1550
    CrossrefPubMedGoogle Scholar
  • 28 Yu P, Zhang J, Ding Y. et al. Dexmedetomidine post-conditioning alleviates myocardial ischemia-reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation. Hum Cell 2022; 35 (03) 836-848
    CrossrefPubMedGoogle Scholar
  • 29 Wang Z, Yao M, Jiang L. et al. Dexmedetomidine attenuates myocardial ischemia/reperfusion-induced ferroptosis via AMPK/GSK-3β/Nrf2 axis. Biomed Pharmacother 2022; 154: 113572
    CrossrefPubMedGoogle Scholar
  • 30 Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22 (04) 266-282
    CrossrefPubMedGoogle Scholar
  • 31 Tao WH, Shan XS, Zhang JX. et al. Dexmedetomidine attenuates ferroptosis-mediated renal ischemia/reperfusion injury and inflammation by inhibiting ACSL4 via α2-AR. Front Pharmacol 2022; 13: 782466
    CrossrefPubMedGoogle Scholar
  • 32 Pan A, Tan Y, Wang Z, Xu G. STAT4 silencing underlies a novel inhibitory role of microRNA-141-3p in inflammation response of mice with experimental autoimmune myocarditis. Am J Physiol Heart Circ Physiol 2019; 317 (03) H531-H540
    CrossrefPubMedGoogle Scholar
  • 33 Mahmoudi-Lamouki R, Kadkhoda S, Hussen BM, Ghafouri-Fard S. Emerging role of miRNAs in the regulation of ferroptosis. Front Mol Biosci 2023; 10: 1115996
    CrossrefPubMedGoogle Scholar
  • 34 Su Q, Liu Y, Lv XW. et al. Inhibition of lncRNA TUG1 upregulates miR-142–3p to ameliorate myocardial injury during ischemia and reperfusion via targeting HMGB1- and Rac1-induced autophagy. J Mol Cell Cardiol 2019; 133: 12-25
    CrossrefPubMedGoogle Scholar
  • 35 American Physiological Society. Corrigendum. Am J Physiol Heart Circ Physiol 2020; 318 (03) H729
    CrossrefPubMedGoogle Scholar
  • 36 Shan W, Chen W, Zhao X. et al. Long noncoding RNA TUG1 contributes to cerebral ischaemia/reperfusion injury by sponging mir-145 to up-regulate AQP4 expression. J Cell Mol Med 2020; 24 (01) 250-259
    CrossrefPubMedGoogle Scholar
  • 37 Xu Y, Niu Y, Li H, Pan G. Downregulation of lncRNA TUG1 attenuates inflammation and apoptosis of renal tubular epithelial cell induced by ischemia-reperfusion by sponging miR-449b-5p via targeting HMGB1 and MMP2. Inflammation 2020; 43 (04) 1362-1374
    CrossrefPubMedGoogle Scholar
  • 38 Lekva T, Michelsen AE, Roland MCP. et al. Increased ferroptosis in leukocytes from preeclamptic women involving the long non-coding taurine upregulated gene 1 (TUG1). J Intern Med 2024; 295 (02) 181-195
    CrossrefPubMedGoogle Scholar
  • 39 Sun Z, Wu J, Bi Q, Wang W. Exosomal lncRNA TUG1 derived from human urine-derived stem cells attenuates renal ischemia/reperfusion injury by interacting with SRSF1 to regulate ASCL4-mediated ferroptosis. Stem Cell Res Ther 2022; 13 (01) 297
    CrossrefPubMedGoogle Scholar