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Involvement of CD44 and MAPK14-mediated ferroptosis in hemorrhagic shock

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Abstract

To elucidate the induction of ferroptotic pathways and the transcriptional modulation of pivotal genes in the context of hemorrhagic shock. The R software was used to analyze the GSE64711 dataset, isolating genes relevant to ferroptosis. Enrichment analyses and protein interaction networks were assembled. Using WGCNA hub genes were identified and intersected with ferroptosis-related genes, highlighting hub genes CD44 and MAPK14. In a rat hemorrhagic shock model, cardiac ROS, Fe2+, MDA, and GSH levels were assessed. Key ferroptotic proteins (SLC7A11/GPX4) in myocardial tissues were examined via western blot. Hub genes, CD44 and MAPK14, expressions were confirmed through immunohistochemistry. Analyzing the GSE64711 dataset revealed 337 differentially expressed genes, including 12 linked to ferroptosis. Enrichment analysis highlighted pathways closely related to ferroptosis. Using Genemania, we found these genes mainly affect ROS metabolism and oxidative stress response. WGCNA identified CD44 and MAPK14 as hub genes. Rat myocardial tissue validation showed significant cardiac damage and elevated ROS and MDA levels, and decreased GSH levels in the hemorrhagic shock model. The ferroptotic pathway SLC7A11/GPX4 was activated, and immunohistochemistry showed a significant increase in the expression levels of CD44 and MAPK14 in the hemorrhagic shock rat model. We demonstrated the presence of tissue ferroptosis in hemorrhagic shock by combining bioinformatics analysis with in vivo experimentation. Specifically, we observed the activation of the SLC7A11/GPX4 ferroptotic pathway. Further, CD44 and MAPK14 were identified as hub genes in hemorrhagic shock.

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References

  1. Cannon JW (2018) Hemorrhagic shock. N Engl J Med 378(4):370–379

    Article  PubMed  Google Scholar 

  2. Ahmad FB, Anderson RN (2021) The leading causes of death in the US for 2020. JAMA 325(18):1829–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rhee P, Joseph B, Pandit V, Aziz H, Vercruysse G, Kulvatunyou N, Friese RS (2014) Increasing trauma deaths in the United States. Ann Surg 260(1):13–21

    Article  PubMed  Google Scholar 

  4. Moreira MA, Irigoyen MC, Saad KR, Saad PF, Koike MK, Montero EF, Martins JL (2016) N-acetylcysteine reduces the renal oxidative stress and apoptosis induced by hemorrhagic shock. J Surg Res 203(1):113–120

    Article  CAS  PubMed  Google Scholar 

  5. Zhang LM, Zhang DX, Fu L, Li Y, Wang XP, Qi MM, Li CC, Song PP, Wang XD, Kong XJ (2019) Carbon monoxide-releasing molecule-3 protects against cortical pyroptosis induced by hemorrhagic shock and resuscitation via mitochondrial regulation. Free Radic Biol Med 141:299–309

    Article  CAS  PubMed  Google Scholar 

  6. Kleinveld DJB, Wirtz MR, van den Brink DP, Maas MAW, Roelofs J, Goslings JC, Hollmann MW, Juffermans NP (2019) Use of a high platelet-to-RBC ratio of 2:1 is more effective in correcting trauma-induced coagulopathy than a ratio of 1:1 in a rat multiple trauma transfusion model. Intensive Care Med Exp 7(Suppl 1):42

    Article  PubMed  PubMed Central  Google Scholar 

  7. Malgras B, Prunet B, Lesaffre X, Boddaert G, Travers S, Cungi PJ, Hornez E, Barbier O, Lefort H, Beaume S et al (2017) Damage control: concept and implementation. J Visc Surg 154(Suppl 1):S19–S29

    Article  PubMed  Google Scholar 

  8. Sung CW, Sun JT, Huang EP, Shin SD, Song KJ, Hong KJ, Jamaluddin SF, Son DN, Hsieh MJ, Ma MH et al (2022) Association between prehospital fluid resuscitation with crystalloids and outcome of trauma patients in Asia by a cross-national multicenter cohort study. Sci Rep 12(1):4100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xl L, Gy Z (2022) Ferroptosis in sepsis: the mechanism, the role and the therapeutic potential. Front Immunol 13:956361

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yan HF, Tuo QZ, Yin QZ, Lei P (2020) The pathological role of ferroptosis in ischemia/reperfusion-related injury. Zool Res 41(3):220–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, Koppula P, Wu S, Zhuang L, Fang B et al (2021) DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593(7860):586–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282

    Article  PubMed  PubMed Central  Google Scholar 

  14. Conrad M, Pratt DA (2019) The chemical basis of ferroptosis. Nat Chem Biol 15(12):1137–1147

    Article  CAS  PubMed  Google Scholar 

  15. Liu J, Kang R, Tang D (2022) Signaling pathways and defense mechanisms of ferroptosis. FEBS J 289(22):7038–7050

    Article  CAS  PubMed  Google Scholar 

  16. Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA et al (2003) Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nat Genet 35(4):331–340

    Article  CAS  PubMed  Google Scholar 

  17. van der Pol A, van Gilst WH, Voors AA, van der Meer P (2019) Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail 21(4):425–435

    Article  PubMed  Google Scholar 

  18. Tang D, Chen X, Kang R, Kroemer G (2021) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125

    Article  CAS  PubMed  Google Scholar 

  19. Rixen D, Siegel JH (2005) Bench-to-bedside review: oxygen debt and its metabolic correlates as quantifiers of the severity of hemorrhagic and post-traumatic shock. Crit Care 9(5):441–453

    Article  PubMed  PubMed Central  Google Scholar 

  20. Duan C, Kuang L, Xiang X, Zhang J, Zhu Y, Wu Y, Yan Q, Liu L, Li T (2020) Activated Drp1-mediated mitochondrial ROS influence the gut microbiome and intestinal barrier after hemorrhagic shock. Aging (Albany NY) 12(2):1397–1416

    Article  CAS  PubMed  Google Scholar 

  21. Vanzant EL, Hilton RE, Lopez CM, Zhang J, Ungaro RF, Gentile LF, Szpila BE, Maier RV, Cuschieri J, Bihorac A et al (2015) Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock. Crit Care 19(1):77

    Article  PubMed  PubMed Central  Google Scholar 

  22. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP (2011) Molecular signatures database (MSigDB) 3.0. Bioinformatics 27(12):1739–1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Franz M, Rodriguez H, Lopes C, Zuberi K, Montojo J, Bader GD, Morris Q (2018) GeneMANIA update 2018. Nucleic Acids Res 46(W1):W60–W64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abdullah S, Karim M, Legendre M, Rodriguez L, Friedman J, Cotton-Betteridge A, Drury R, Packer J, Guidry C, Duchesne J et al (2021) Hemorrhagic shock and resuscitation causes glycocalyx shedding and endothelial oxidative stress preferentially in the lung and intestinal vasculature. Shock 56(5):803–812

    Article  CAS  PubMed  Google Scholar 

  26. Yao H, Gao Y, Han J, Wang Y, Cai J, Rui Y, Ge X (2022) MKK4 knockdown plays a protective role in hemorrhagic shock-induced liver injury through the JNK pathway. Oxid Med Cell Longev 2022:5074153

    Article  PubMed  PubMed Central  Google Scholar 

  27. Liu R, Wang SM, Liu XQ, Guo SJ, Wang HB, Hu S, Zhou FQ, Sheng ZY (2016) Pyruvate alleviates lipid peroxidation and multiple-organ dysfunction in rats with hemorrhagic shock. Am J Emerg Med 34(3):525–530

    Article  CAS  PubMed  Google Scholar 

  28. Jia B, Ye J, Gan L, Li R, Zhang M, Sun D, Weng L, Xiong Y, Xu J, Zhang P et al (2022) Mitochondrial antioxidant SkQ1 decreases inflammation following hemorrhagic shock by protecting myocardial mitochondria. Front Physiol 13:1047909

    Article  PubMed  PubMed Central  Google Scholar 

  29. Moon DH, Kang DY, Haam SJ, Yumoto T, Tsukahara K, Yamada T, Nakao A, Lee S (2019) Hydrogen gas inhalation ameliorates lung injury after hemorrhagic shock and resuscitation. J Thorac Dis 11(4):1519–1527

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171(2):273–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liang D, Minikes AM, Jiang X (2022) Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 82(12):2215–2227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fang JY, Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6(5):322–327

    Article  CAS  PubMed  Google Scholar 

  33. Li L, Hao Y, Zhao Y, Wang H, Zhao X, Jiang Y, Gao F (2018) Ferroptosis is associated with oxygen-glucose deprivation/reoxygenation-induced Sertoli cell death. Int J Mol Med 41(5):3051–3062

    CAS  PubMed  Google Scholar 

  34. Yang L, Jiang L, Sun X, Li J, Wang N, Liu X, Yao X, Zhang C, Deng H, Wang S et al (2022) DEHP induces ferroptosis in testes via p38alpha-lipid ROS circulation and destroys the BTB integrity. Food Chem Toxicol 164:113046

    Article  CAS  PubMed  Google Scholar 

  35. Han S, Wang Y, Ma J, Wang Z, Wang HD, Yuan Q (2020) Sulforaphene inhibits esophageal cancer progression via suppressing SCD and CDH3 expression, and activating the GADD45B-MAP2K3-p38-p53 feedback loop. Cell Death Dis 11(8):713

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liu T, Jiang L, Tavana O, Gu W (2019) The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res 79(8):1913–1924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lei G, Zhuang L, Gan B (2022) Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 22(7):381–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Muller S, Sindikubwabo F, Caneque T, Lafon A, Versini A, Lombard B, Loew D, Wu TD, Ginestier C, Charafe-Jauffret E et al (2020) CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat Chem 12(10):929–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mees ST, Gwinner M, Marx K, Faendrich F, Schroeder J, Haier J, Kahlke V (2008) Influence of sex and age on morphological organ damage after hemorrhagic shock. Shock 29(6):670–674

    Article  PubMed  Google Scholar 

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82274283), the High-level Public Healh Technical Personnel Construction Project Training Plan (No. XKGG-01-030), the Research on Prevention and Treatment of 2019-nCov with Traditional Chinese Medicine (No. 2020YFC0841500), and Beijing Hospitals Authority Youth Programme (Code: QML20231002).

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Author notes

  1. Haoran Ye and Shasha He have contributed equally and fully in this study.

Authors and Affiliations

  1. Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China

    Haoran Ye, Shasha He, Yuan Du, Yuchen Wang, Chunxia Zhao, Yueting Jin, Fangyu Liu & Yuhong Guo

  2. Beijing Institute of Chinese Medicine, Beijing, China

    Haoran Ye, Shasha He, Chunxia Zhao, Yueting Jin & Yuhong Guo

  3. Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, Beijing, China

    Haoran Ye, Shasha He, Chunxia Zhao, Yueting Jin & Yuhong Guo

  4. Beijing University of Chinese Medicine, Beijing, China

    Yuan Du, Yuchen Wang & Fangyu Liu

  5. Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Yahui Hu

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Contributions

All authors listed have significantly contributed to the development and the writing of this article. HRY and SSH provided ideas, conducted data retrieval and carried out the experiment. YD and YCW suggested for the analysis. CXZ, YHH, YTJ and FYL visualized the data and advised on the study. YHG designed and supervised the study.

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Correspondence to Yuhong Guo.

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The animal experimental protocol was approved by the Animal Ethics Committee of Beijing Hospital of Traditional Chinese Medicine, Capital Medical University (Approval No. BJTCM-R-20220501).

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Ye, H., He, S., Du, Y. et al. Involvement of CD44 and MAPK14-mediated ferroptosis in hemorrhagic shock. Apoptosis 29, 154–168 (2024). https://doi.org/10.1007/s10495-023-01894-6

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