The Journal of Practical Medicine >
ALKBH5 reduce septic-induced myocardial dysfunction by regulating the TRAF1/NF-κB pathway
Received date: 2024-04-25
Online published: 2024-09-13
Objective To investigate the molecular mechanism of ALKBH5 reducing sepsis-induced myocardial dysfunction （SIMD）. Methods The expression levels of ALKBH5 and TRAF1 in the blood of 50 SIMD patients and 50 healthy individuals were detected using reverse transcription fluorescence quantitative polymerase chain reaction （RT-qPCR）， and the correlation between their expression levels was analyzed by person analysis； In vitro experiments， H9C2 myocardial cells were divided into 7 groups according to over expression of TARF1 and knockdown ALKBH5. The molecular mechanism of ALKBH5 targeting TRAF1 to regulate lipopolysaccharide （LPS）induced myocardial cell damage was studied through experiments such as CCK8， ELISA， and Western blot； In the in vivo experiment of rats， LPS induced rats were divided into 6 groups according to over expression of TARF1 and knockdown ALKBH5. Experimental methods such as colorimetry， ELISA， Western blot， HE staining， and immunohistochemistry were used to study the mechanism of ALKBH5 targeting TRAF1 through NF- κB pathway in reducing myocardial cell damage. Results The expression levels of ALKBH5 and TRAF 1 were downregulated in SIMD， and the Pearson analysis showed a positive correlation between them（P < 0.001）； In vitro experiments showed that overexpression of TRAF1 promotes cell proliferation， inhibits the expression of inflammatory factors and proteins involved in the NF- κB pathway， and knockdown ALKBH5 obtain the opposite resulst； In vivo experiments in rats showed that knockdown ALKBH5 promotes injury in cardiomyocytes， expression of inflammatory factors and NF- κB-related pathway proteins， and nuclear translocation of NF-κB p65 protein， but the overexpression of TRAF 1 yielded the opposite results. Conclusion ALKBH5 increases the stability of TRAF1 by reducing its methylation， thereby inhibiting NF- κB pathway， thereby reducing SIMD.
Key words： sepsis -induced myocardial dysfunction; ALKBH5; TRAF1; NF-κB
Min LIU , Xiyun CHEN , Jianlei Lü , Jie. FENG . ALKBH5 reduce septic-induced myocardial dysfunction by regulating the TRAF1/NF-κB pathway[J]. The Journal of Practical Medicine, 2024 , 40(17) : 2381 -2389 . DOI: 10.3969/j.issn.1006-5725.2024.17.005
| 1 | KOTECHA A， VALLABHAJOSYULA S， COVILLE H H， et al. Cardiorenal syndrome in sepsis： A narrative review［J］. J Crit Care， 2018， 43：122-127. doi:10.1016/j.jcrc.2017.08.044 |
| 2 | INNOCENTI F， PALMIERI V， GUZZO A， et al. SOFA score and left ventricular systolic function as predictors of short-term outcome in patients with sepsis［J］. Intern Emerg Med， 2018， 13（1）： 51-58. doi:10.1007/s11739-016-1579-3 |
| 3 | L'HEUREUX M， STERNBERG M， BRATH L， et al. Sepsis-Induced Cardiomyopathy： A Comprehensive Review［J］. Curr Cardiol Rep， 2020， 22（5）：35. doi:10.1007/s11886-020-01277-2 |
| 4 | HOLLENBERG S M， SINGER M. Pathophysiology of sepsis-induced cardiomyopathy［J］. Nat Rev Cardiol， 2021， 18（6）： 424-434. doi:10.1038/s41569-020-00492-2 |
| 5 | WANG J Y， WANG J Q， GU Q， et al. The biological function of m6A demethylase ALKBH5 and its role in human disease［J］. Cancer Cell Int， 2020， 20：347. doi:10.1186/s12935-020-01450-1 |
| 6 | HAN Z B， WANGX X， XU Z H， et al. ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1［J］. Theranostics， 2021， 11（6）：3000-3016. doi:10.7150/thno.47354 |
| 7 | 杨帆，武菲菲，苏洁，等. 姜黄素通过AMPK/FUNDC1缓解LPS诱导的心肌细胞损伤［J］. 医学研究杂志，2022，51（19）：30-36． |
| 8 | 陈思聪，张雁斌，马扬杰. 人参皂苷Rg1对脓毒症所致心肌损伤大鼠HMGB1/NF-κB通路的影响［J］. 中国免疫学杂志，2023，39（8）：1671-1677． doi:10.3969/j.issn.1000-484X.2023.08.019 |
| 9 | 敖雪，苏醒，侯宇，等. 基于p38MAPK/NF-κB研究miR-146a干预脓毒性心肌病的分子机制［J］. 实用医学杂志，2023，39（24）：3188-3194． doi:10.3969/j.issn.1006-5725.2023.24.007 |
| 10 | 黄颖，唐立丽，关于琳，等. 脓毒症心肌损伤发病机制及治疗研究进展［J］. 实用医学杂志，2023，39（14）：1848-1852． doi:10.3969/j.issn.1006-5725.2023.14.021 |
| 11 | ZHANG J， GUO S， PIAO H Y， et al. ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1［J］. J Physiol Biochem， 2019，75（3）：379-389. doi:10.1007/s13105-019-00690-8 |
| 12 | ZHU H T， GAN X L， JIANG X W， et al. ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2［J］. J Exp Clin Cancer Res， 2019， 38（1）： 163. doi:10.1186/s13046-019-1159-2 |
| 13 | ZHANG C Z， SAMANTA D， LU H Q， et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m?A-demethylation of NANOG mRNA［J］. Proc Natl Acad Sci U S A， 2016， 113 （14）： E2047-E2056. doi:10.1073/pnas.1602883113 |
| 14 | ZHOU J， ZHANG X， HU J， et al. M6A demethylase ALKBH5 controls CD4+T cell pathogenicity and promotes autoimmunity［J］. Sci Adv， 2021， 7（25）：eabg0470. doi:10.1126/sciadv.abg0470 |
| 15 | GAO Y， ZIMMER J T， VASIC R，et al. ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through mA modification-mediated RNA stability control［J］. Cell Rep， 2023， 42（10）：113163. doi:10.1016/j.celrep.2023.113163 |
| 16 | LANDFORS M， NAKKEN S， FUSSER M， et al. Sequencing of FTO and ALKBH5 in men undergoing infertility work-up identifies an infertility-associated variant and two missense mutations［J］. Fertil Steril， 2016， 105（5）： 1170-1179.e5. doi:10.1016/j.fertnstert.2016.01.002 |
| 17 | YU J J， SHEN L J， LIU Y L， et al. The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling［J］. Mol Cell Biochem， 2020， 463（1/2）： 203-210. doi:10.1007/s11010-019-03641-5 |
| 18 | TANG C， KLUKOVICH R， PENG H Y， et al. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3'-UTR mRNAs in male germ cells［J］. Proc Natl Acad Sci U S A， 2018， 115（2）： E325-E333. doi:10.1073/pnas.1717794115 |
| 19 | 吴春阳. 去甲基化酶ALKBH5依赖m6A修饰调控E2F8/PI3K/AKT信号轴抑制骨肉瘤恶性表型的机制研究［D］. 南昌：南昌大学，2023． |
| 20 | LIU Y， SONG R J， ZHAO L， et al. m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration［J］. Signal Transduct Target Ther， 2022， 7（1）： 194. doi:10.1038/s41392-022-01020-z |
| 21 | PARBELL G P， TANG B M， NALOS M， et al. Identifying key regulatory genes in the whole blood of septic patients to monitor underlying immune dysfunctions［J］. Shock， 2013， 40（3）：166-174. doi:10.1097/shk.0b013e31829ee604 |
| 22 | TANG X， ZHANG L， WEI W. Roles of TRAFs in NF-κB signaling pathways mediated by BAFF［J］. Immunol Lett， 2018， 196：113-118. doi:10.1016/j.imlet.2018.01.010 |
| 23 | 张鹏. TRAF1转导跨膜TNF-α反向信号组成性活化NF-κB通路及其对白血病细胞耐药的影响［D］. 武汉：华中科技大学，2021． |
| 24 | QU J W， HOU Y， CHEN Q X， et al. RNA demethylase ALKBH5 promotes tumorigenesis in multiple myeloma via TRAF1-mediated activation of NF-κB and MAPK signaling pathways［J］. Oncogene， 2022， 41（3）：400-413. doi:10.1038/s41388-021-02095-8 |
| 25 | 周颖，蒋大军，田勇，等. 抑制TRAF6调节炎症和自噬改善脓毒症小鼠的心肌损伤和心功能［J］. 实用医学杂志，2024，40（5）：608-416． |
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