Skip to content
2000
Volume 28, Issue 14
  • ISSN: 1386-2073
  • E-ISSN: 1875-5402

Abstract

Background

Melatonin (MT) has been demonstrated to have cardioprotective effects. Nevertheless, the precise mechanism through which MT provides protection against the etiology of LPS-induced myocardial injury remains uncertain. In this investigation, our objective was to explore the impact of MT on LPS-induced myocardial injury in an setting.

Methods

H9C2 cells were categorized into four groups: a control group (H9C2 group), an MT group, an LPS group, and an MT + LPS group. The H9C2 group received treatment with sterile saline solution, the LPS group was exposed to 5 μg/mL LPS for 24 hours, the MT + LPS group underwent pretreatment with 150 μmol/L MT for 2 hours, followed by exposure to 5 μg/mL LPS for 24 hours, and the MT group received only 150 μmol/L MT for 2 hours. Cell viability and lactate dehydrogenase (LDH) release were assessed using the CCK-8 assay and LDH activity assay, respectively. The levels of reactive oxygen species (ROS) were quantified in each group of cells, and the percentage of propidium iodide (PI)-stained apoptotic cells was determined by flow cytometry. The mRNA levels of caspase11, GSDMD, and IL-18 in each group of cells were quantified.

Results

MT treatment significantly protected H9C2 cells from LPS-induced damage, as evidenced by decreased LDH release. LPS treatment markedly increased ROS levels in H9C2 cells, which were subsequently reduced by MT. LPS caused a substantial decrease in superoxide dismutase (SOD) activity and a significant increase in malondialdehyde (MDA) levels, while MT treatment significantly reversed these effects. Additionally, MT markedly enhanced the proportion of viable H9C2 cells compared to LPS-treated controls, as evidenced by the PI staining assay. LPS upregulated both mRNA levels and protein levels of IL-18 in H9C2 cells. However, MT treatment effectively mitigated this LPS-induced increase. Furthermore, MT significantly decreased LPS-induced protein levels of cleaved-caspase 11 and GSDMD-N in H9C2 cells.

Conclusion

Overall, our findings suggest that MT inhibits the Caspase11-GSDMD signaling pathway pyroptosis-related proteins (caspase-11 and GSDMD-N) and reduces the expression of inflammation-related cytokines (IL-18), thereby exerting a protective effect on H9C2 cells after LPS injury.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cchts/10.2174/0113862073284989240510062817
2024-07-10
2025-11-04

  • From This Site

    /content/journals/cchts/10.2174/0113862073284989240510062817
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. AngusD. Pires PereiraC. SilvaE. Epidemiology of severe sepsis around the world.Endocr. Metab. Immune Disord. Drug Targets20066220721210.2174/187153006777442332 16787296
     [Google Scholar]
  2. ZhengZ. MaH. ZhangX. TuF. WangX. HaT. FanM. LiuL. XuJ. YuK. WangR. KalbfleischJ. KaoR. WilliamsD. LiC. Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis.J. Infect. Dis.201721591396140610.1093/infdis/jix138 28368517
     [Google Scholar]
  3. OkaT. HikosoS. YamaguchiO. TaneikeM. TakedaT. TamaiT. OyabuJ. MurakawaT. NakayamaH. NishidaK. AkiraS. YamamotoA. KomuroI. OtsuK. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.Nature2012485739725125510.1038/nature10992 22535248
     [Google Scholar]
  4. MerxM.W. WeberC. Sepsis and the Heart.Circulation2007116779380210.1161/CIRCULATIONAHA.106.678359 17698745
     [Google Scholar]
  5. KawaguchiM. TakahashiM. HataT. KashimaY. UsuiF. MorimotoH. IzawaA. TakahashiY. MasumotoJ. KoyamaJ. HongoM. NodaT. NakayamaJ. SagaraJ. TaniguchiS. IkedaU. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury.Circulation2011123659460410.1161/CIRCULATIONAHA.110.982777 21282498
     [Google Scholar]
  6. WangP. ZhangW. FengZ. ZhangJ. SunY. ZhangW. LDL induced NLRC3 inflammasome activation in cardiac fibroblasts contributes to cardiomyocytic dysfunction.Mol. Med. Rep.202124152610.3892/mmr.2021.12165 34036387
     [Google Scholar]
  7. SunY. YaoX. ZhangQ.J. ZhuM. LiuZ.P. CiB. XieY. CarlsonD. RothermelB.A. SunY. LevineB. HillJ.A. WolfS.E. MineiJ.P. ZangQ.S. Beclin-1-dependent autophagy protects the heart during sepsis.Circulation2018138202247226210.1161/CIRCULATIONAHA.117.032821 29853517
     [Google Scholar]
  8. AliT. RahmanS.U. HaoQ. LiW. LiuZ. Ali ShahF. MurtazaI. ZhangZ. YangX. LiuG. LiS. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation.J. Pineal Res.2020692e1266710.1111/jpi.12667 32375205
     [Google Scholar]
  9. PatoliD. MignotteF. DeckertV. DusuelA. DumontA. RieuA. JalilA. Van DongenK. BourgeoisT. GautierT. MagnaniC. Le GuernN. MandardS. BastinJ. DjouadiF. SchaefferC. GuillaumotN. NarceM. NguyenM. GuyJ. DargentA. QuenotJ.P. RiallandM. MassonD. AuwerxJ. LagrostL. ThomasC. Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis.J. Clin. Invest.2020130115858587410.1172/JCI130996 32759503
     [Google Scholar]
  10. TangD. WangH. BilliarT.R. KroemerG. KangR. Emerging mechanisms of immunocoagulation in sepsis and septic shock.Trends Immunol.202142650852210.1016/j.it.2021.04.001 33906793
     [Google Scholar]
  11. HsuC.G. ChávezC.L. ZhangC. SowdenM. YanC. BerkB.C. The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis.Cell Death Differ.20222991790180310.1038/s41418‑022‑00966‑5 35264781
     [Google Scholar]
  12. QiuS. LiuJ. XingF. ‘Hints’ in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death.Cell Death Differ.201724458859610.1038/cdd.2017.24 28362726
     [Google Scholar]
  13. KayagakiN. StoweI.B. LeeB.L. O’RourkeK. AndersonK. WarmingS. CuellarT. HaleyB. Roose-GirmaM. PhungQ.T. LiuP.S. LillJ.R. LiH. WuJ. KummerfeldS. ZhangJ. LeeW.P. SnipasS.J. SalvesenG.S. MorrisL.X. FitzgeraldL. ZhangY. BertramE.M. GoodnowC.C. DixitV.M. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.Nature2015526757566667110.1038/nature15541 26375259
     [Google Scholar]
  14. FeiL. ZhangN. ZhangJ. Mechanism of miR-126 in hypoxia-reoxygenation-induced cardiomyocyte pyroptosis by regulating HMGB1 and NLRP3 inflammasome.Immunopharmacol. Immunotoxicol.202244450050910.1080/08923973.2022.2054819 35297734
     [Google Scholar]
  15. GaoY.L. ZhaiJ.H. ChaiY.F. Recent advances in the molecular mechanisms underlying pyroptosis in sepsis.Mediators Inflamm.201820181710.1155/2018/5823823 29706799
     [Google Scholar]
  16. de DiosC. AbadinX. Roca-AgujetasV. Jimenez-MartinezM. MoralesA. TrullasR. MariM. ColellA. Inflammasome activation under high cholesterol load triggers a protective microglial phenotype while promoting neuronal pyroptosis.Transl. Neurodegener.20231211010.1186/s40035‑023‑00343‑3 36895045
     [Google Scholar]
  17. FenderA.C. KleeschulteS. StolteS. LeineweberK. KamlerM. BodeJ. LiN. DobrevD. Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart.Basic Res. Cardiol.202011521010.1007/s00395‑019‑0771‑9 31912235
     [Google Scholar]
  18. FengW.D. WangY. LuoT. JiaX. ChengC.Q. WangH.J. ZhangM.Q. LiQ.Q. WangX.J. LiY.Y. WangJ.Y. HuangG.R. WangT. XuA.L. Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases.Acta Pharmacol. Sin.202244612381251 36522512
     [Google Scholar]
  19. LiangH. WangB. WangJ. MaB. ZhangW. Pyolysin of Trueperella pyogenes induces pyroptosis and il-1β release in murine macrophages through potassium/nlrp3/caspase-1/gasdermin d pathway.Front. Immunol.20221383245810.3389/fimmu.2022.832458 35371034
     [Google Scholar]
  20. ShiJ. ZhaoY. WangK. ShiX. WangY. HuangH. ZhuangY. CaiT. WangF. ShaoF. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.Nature2015526757566066510.1038/nature15514 26375003
     [Google Scholar]
  21. YanpisetP. ManeechoteC. SriwichaiinS. Siri-AngkulN. ChattipakornS.C. ChattipakornN. Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies.Acta Pharm. Sin. B2023131295310.1016/j.apsb.2022.08.007 36815034
     [Google Scholar]
  22. PiamsiriC. ManeechoteC. JinawongK. ArunsakB. ChunchaiT. NawaraW. ChattipakornS.C. ChattipakornN. GSDMD-mediated pyroptosis dominantly promotes left ventricular remodeling and dysfunction in post-myocardial infarction: A comparison across modes of programmed cell death and mitochondrial involvement.J. Transl. Med.20232111610.1186/s12967‑023‑03873‑6 36627703
     [Google Scholar]
  23. LinJ. LaiX. FanX. YeB. ZhongL. ZhangY. ShaoR. ShiS. HuangW. SuL. YingM. Oridonin protects against myocardial ischemia–reperfusion injury by Inhibiting GSDMD-mediated pyroptosis.Genes20221311213310.3390/genes13112133 36421808
     [Google Scholar]
  24. DrummerC.IV SaaoudF. JhalaN.C. CuetoR. SunY. XuK. ShaoY. LuY. ShenH. YangL. ZhouY. YuJ. WuS. SnyderN.W. HuW. ZhuoJ.J. ZhongY. JiangX. WangH. YangX. Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages.Front. Immunol.202314111388310.3389/fimmu.2023.1113883 36776889
     [Google Scholar]
  25. ShiH. GaoY. DongZ. YangJ. GaoR. LiX. ZhangS. MaL. SunX. WangZ. ZhangF. HuK. SunA. GeJ. GSDMD-mediated cardiomyocyte pyroptosis promotes myocardial I/R injury.Circ. Res.2021129338339610.1161/CIRCRESAHA.120.318629 34015941
     [Google Scholar]
  26. GaoY. ShiH. DongZ. ZhangF. SunA. GeJ. Current knowledge of pyroptosis in heart diseases.J. Mol. Cell. Cardiol.2022171818910.1016/j.yjmcc.2022.07.005 35868567
     [Google Scholar]
  27. SugawaraI. Interleukin-18 (IL-18) and infectious diseases, with special emphasis on diseases induced by intracellular pathogens.Microbes Infect.20002101257126310.1016/S1286‑4579(00)01279‑X 11008115
     [Google Scholar]
  28. VmM. AlS. AaA. AsZ. AvK. RsO. Im, M.; Ga, K. Circulating interleukin-18: Association with IL-8, IL-10 and VEGF serum levels in patients with and without heart rhythm disorders.Int. J. Cardiol.201621510510910.1016/j.ijcard.2016.04.002 27111169
     [Google Scholar]
  29. SunW. HanY. YangS. ZhuangH. ZhangJ. ChengL. FuL. The assessment of interleukin-18 on the risk of coronary heart disease.Med. Chem.202016562663410.2174/1573406415666191004115128 31584380
     [Google Scholar]
  30. YamashitaH. IshikawaM. InoueT. UsamiM. UsamiY. KotaniJ. Interleukin-18 reduces blood glucose and modulates plasma corticosterone in a septic mouse model.Shock201747445546210.1097/SHK.0000000000000747 27648697
     [Google Scholar]
  31. ChandrasekarB. ColstonJ.T. de la RosaS.D. RaoP.P. FreemanG.L. TNF-α and H2O2 induce IL-18 and IL-18Rβ expression in cardiomyocytes via NF-κB activation.Biochem. Biophys. Res. Commun.200330341152115810.1016/S0006‑291X(03)00496‑0 12684057
     [Google Scholar]
  32. YouJ. LiX. DaiF. LiuJ. ZhangQ. GuoW. GSDMD-mediated pyroptosis promotes cardiac remodeling in pressure overload.Clin. Exp. Hypertens.2023451218913810.1080/10641963.2023.2189138 36906959
     [Google Scholar]
  33. QiuZ. HeY. MingH. LeiS. LengY. XiaZ. Lipopolysaccharide (LPS) aggravates high glucose- and hypoxia/reoxygenation-induced injury through activating ROS-dependent NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes.J. Diabetes Res.2019201911210.1155/2019/8151836 30911553
     [Google Scholar]
  34. LiuX. ZhangZ. RuanJ. PanY. MagupalliV.G. WuH. LiebermanJ. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores.Nature2016535761015315810.1038/nature18629 27383986
     [Google Scholar]
  35. FuZ. JiaoY. WangJ. ZhangY. ShenM. ReiterR.J. XiQ. ChenY. Cardioprotective role of melatonin in acute myocardial infarction.Front. Physiol.20201136610.3389/fphys.2020.00366 32411013
     [Google Scholar]
  36. BaiY. YangY. CuiB. LinD. WangZ. MaJ. Temporal effect of melatonin posttreatment on anoxia/reoxygenation injury in H9c2 cells.Cell Biol. Int.202246463764810.1002/cbin.11759 34989460
     [Google Scholar]
  37. ReiterR.J. Rosales-CorralS. TanD.X. JouM.J. GalanoA. XuB. Melatonin as a mitochondria-targeted antioxidant: One of evolution’s best ideas.Cell. Mol. Life Sci.201774213863388110.1007/s00018‑017‑2609‑7 28864909
     [Google Scholar]
  38. CarrascalL. Nunez-AbadesP. AyalaA. CanoM. Role of melatonin in the inflammatory process and its therapeutic potential.Curr. Pharm. Des.201824141563158810.2174/1381612824666180426112832 29701146
     [Google Scholar]
  39. WuJ. YangY. GaoY. WangZ. MaJ. Melatonin attenuates anoxia/reoxygenation injury by inhibiting excessive mitophagy through the MT2/SIRT3/FoxO3a signaling pathway in h9c2 cells.Drug Des. Devel. Ther.2020142047206010.2147/DDDT.S248628 32546969
     [Google Scholar]
  40. PanP. ZhangH. SuL. WangX. LiuD. Melatonin balance the autophagy and apoptosis by regulating UCP2 in the LPS-induced cardiomyopathy.Molecules201823367510.3390/molecules23030675 29547569
     [Google Scholar]
  41. DiS. WangZ. HuW. YanX. MaZ. LiX. LiW. GaoJ. The protective effects of melatonin against lps-induced septic myocardial injury: A potential role of AMPK-mediated autophagy.Front. Endocrinol.20201116210.3389/fendo.2020.00162 32373063
     [Google Scholar]
  42. ZhongJ. TanY. LuJ. LiuJ. XiaoX. ZhuP. ChenS. ZhengS. ChenY. HuY. GuoZ. Therapeutic contribution of melatonin to the treatment of septic cardiomyopathy: A novel mechanism linking Ripk3-modified mitochondrial performance and endoplasmic reticulum function.Redox Biol.20192610128710.1016/j.redox.2019.101287 31386965
     [Google Scholar]
  43. WenL. WangM. LuoP. MengX. ZhaoM. Melatonin exerts cardioprotective effects by inhibiting NLRP3 inflammasome-induced pyroptosis in mice following myocardial infarction.Oxid. Med. Cell. Longev.2021202111410.1155/2021/5387799 34512865
     [Google Scholar]
  44. ThackerayJ.T. HupeH.C. WangY. BankstahlJ.P. BerdingG. RossT.L. BauersachsJ. WollertK.C. BengelF.M. Myocardial inflammation predicts remodeling and neuroinflammation after myocardial infarction.J. Am. Coll. Cardiol.201871326327510.1016/j.jacc.2017.11.024 29348018
     [Google Scholar]
  45. MaityJ. DeyT. BanerjeeA. ChattopadhyayA. DasA.R. BandyopadhyayD. Melatonin ameliorates myocardial infarction in obese diabetic individuals: The possible involvement of macrophage apoptotic factors.J. Pineal Res.2023742e1284710.1111/jpi.12847 36456538
     [Google Scholar]
  46. SuZ.D.Z. WeiX.B. FuY.B. XuJ. WangZ.H. WangY. CaoJ.F. HuangJ.L. YuD.Q. Melatonin alleviates lipopolysaccharide-induced myocardial injury by inhibiting inflammation and pyroptosis in cardiomyocytes.Ann. Transl. Med.20219541310.21037/atm‑20‑8196 33842634
     [Google Scholar]
/content/journals/cchts/10.2174/0113862073284989240510062817
Loading
The Protective Effect of Melatonin on LPS-Induced Myocardial Injury via the Caspase-11/GSDMD Pathway
Comb Chem High Throughput Screen 28, 2433 (2025); https://doi.org/10.2174/0113862073284989240510062817
/content/journals/cchts/10.2174/0113862073284989240510062817
/content/journals/cchts/10.2174/0113862073284989240510062817
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): caspase-11/GSDMD signalling pathway; cell pyroptosis; inflammation; Melatonin; myocardial injury; oxidative stress

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test