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2000
Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
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Abstract

Background

Cinaciguat is a soluble Guanylyl Cyclase (sGC) activator that plays a crucial role in cardiovascular diseases. Previous research has shown that cinaciguat is involved in the progression of cardiomyopathy, which encompasses cardiac enlargement, heart dysfunction, and doxorubicin-induced heart damage. However, its therapeutic potential in sepsis-induced cardiomyopathy remains unknown.

Objectives

This study examined the impact of cinaciguat on Lipopolysaccharide (LPS)-induced myocardial injury and the underlying molecular mechanisms.

Methods

The mice model was established through intraperitoneal injection of LPS (10 mg/kg), and an model was generated by stimulating H9c2 cells with LPS (10 μg/ml) for 12 h. Subsequently, the sGC activator cinaciguat was used to assess its effects on LPS-induced cardiac injury. Additionally, echocardiography was conducted 12 hours after modeling to analyze cardiac function in mice. We used various methods to evaluate inflammation, and apoptosis, including Enzyme-Linked Immunosorbent Assay (ELISA), terminal deoxynucleotidyl transferase-mediated deoxyuridine Triphosphate Nick End Labeling (TUNEL) assay, Hematoxylin and Eosin (HE) staining, western blotting and Real-Time Polymerase Chain Reaction (RT-PCR). Additionally, the protein kinase cGMP-dependent 1 (PRKG1)/cAMP-Response Element Binding protein (CREB) signaling pathway and Mitochondrial Ferritin (FtMt) in LPS-induced cardiac injury was assessed western blot analysis.

Results

LPS-induced cardiac dysfunction and increased levels of cardiac injury markers Cardiac Troponin T (cTnT) . This change was accompanied by an increase in inflammatory cytokines through Interleu-1β (IL-1β), Tumor Necrosis Factor α (TNF-α), and Interleu-6 (IL-6). The expression of apoptosis, such as cleaved caspase-3, Bax, and Bcl-2, was also upregulated. However, these effects were reversed via treatment with cinaciguat. Additionally, cinaciguat alleviated LPS-induced cardiac inflammation and apoptosis by activating the PRKG1/CREB signaling pathway, and promoting FtMt expression. The same results were also obtained in H9c2 cardiomyocytes.

Conclusion

We demonstrated that cinaciguat alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the PRKG1/CREB/FtMt pathway, thereby protecting against LPS-induced cardiac injury. This study identified a new strategy for treating cardiac injury caused by sepsis.

© 2024 The Author(s).
© 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-09-28

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References

  1. SchmochT. MöhnleP. WeigandM.A. BriegelJ. BauerM. BloosF. MeybohmP. KehD. LöfflerM. ElkeG. BrennerT. BogatschH. The prevalence of sepsis-induced coagulopathy in patients with sepsis - A secondary analysis of two German multicenter randomized controlled trials.Ann. Intensive Care2023131310.1186/s13613‑022‑01093‑736635426
     [Google Scholar]
  2. XieQ. YiQ. ZhuJ. TanB. XiangH. WangR. LiuH. ChenT. XuH. Protective role of triiodothyronine in sepsis‑induced cardiomyopathy through phospholamban downregulation.Int. J. Mol. Med.20255534710.3892/ijmm.2025.548839821325
     [Google Scholar]
  3. LiuY.C. YuM.M. ShouS.T. ChaiY.F. Sepsis-induced cardiomyopathy: Mechanisms and treatments.Front. Immunol.20178102110.3389/fimmu.2017.0102128970829
     [Google Scholar]
  4. SongM.J. LeeS.H. LeemA.Y. KimS.Y. ChungK.S. KimE.Y. JungJ.Y. KangY.A. KimY.S. ChangJ. ParkM.S. Predictors and outcomes of sepsis-induced cardiomyopathy in critically ill patients.Acute Crit. Care2020352677610.4266/acc.2020.0002432407613
     [Google Scholar]
  5. HollenbergS.M. SingerM. Pathophysiology of sepsis-induced cardiomyopathy.Nat. Rev. Cardiol.202118642443410.1038/s41569‑020‑00492‑233473203
     [Google Scholar]
  6. LelubreC. VincentJ.L. Mechanisms and treatment of organ failure in sepsis.Nat. Rev. Nephrol.201814741742710.1038/s41581‑018‑0005‑729691495
     [Google Scholar]
  7. LiuH. HuQ. RenK. WuP. WangY. LvC. ALDH2 mitigates LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING pathway.Mol. Med.202329117110.1186/s10020‑023‑00769‑538124089
     [Google Scholar]
  8. MedzhitovR. The spectrum of inflammatory responses.Science202137465711070107510.1126/science.abi520034822279
     [Google Scholar]
  9. AndrabiS.M. SharmaN.S. KaranA. ShahriarS.M.S. CordonB. MaB. XieJ. Nitric oxide: Physiological functions, delivery, and biomedical applications.Adv. Sci.20231030230325910.1002/advs.20230325937632708
     [Google Scholar]
  10. SharinaI. MartinE. Cellular factors that shape the activity or function of nitric oxide-stimulated soluble guanylyl cyclase.Cells202312347110.3390/cells1203047136766813
     [Google Scholar]
  11. HorstB.G. MarlettaM.A. Physiological activation and deactivation of soluble guanylate cyclase.Nitric Oxide201877657410.1016/j.niox.2018.04.01129704567
     [Google Scholar]
  12. StaschJ.P. PacherP. EvgenovO.V. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.Circulation2011123202263227310.1161/CIRCULATIONAHA.110.98173821606405
     [Google Scholar]
  13. LappH. MitrovicV. FranzN. HeuerH. BuerkeM. WolfertzJ. MueckW. UngerS. WensingG. FreyR. Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure.Circulation2009119212781278810.1161/CIRCULATIONAHA.108.80029219451356
     [Google Scholar]
  14. SalloumF.N. DasA. SamiduraiA. HokeN.N. ChauV.Q. OckailiR.A. StaschJ.P. KukrejaR.C. Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: Role of hydrogen sulfide.Am. J. Physiol. Heart Circ. Physiol.20123026H1347H135410.1152/ajpheart.00544.201122268103
     [Google Scholar]
  15. MátyásC. NémethB.T. OláhA. HidiL. BirtalanE. KellermayerD. RuppertM. Korkmaz-IcözS. KökényG. HorváthE.M. SzabóG. MerkelyB. RadovitsT. The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus.Cardiovasc. Diabetol.201514114510.1186/s12933‑015‑0309‑x26520063
     [Google Scholar]
  16. RüdebuschJ. BenknerA. NathN. FleuchL. KaderaliL. GrubeK. KlingelK. EcksteinG. MeitingerT. FielitzJ. FelixS.B. Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling.Br. J. Pharmacol.2022179112430244210.1111/bph.1533333247945
     [Google Scholar]
  17. VandendriesscheB. RoggeE. GoossensV. VandenabeeleP. StaschJ.P. BrouckaertP. CauwelsA. The soluble guanylate cyclase activator BAY 58-2667 protects against morbidity and mortality in endotoxic shock by recoupling organ systems.PLoS One201388e7215510.1371/journal.pone.007215524015214
     [Google Scholar]
  18. MarchiS. GuilbaudE. TaitS.W.G. YamazakiT. GalluzziL. Mitochondrial control of inflammation.Nat. Rev. Immunol.202323315917310.1038/s41577‑022‑00760‑x35879417
     [Google Scholar]
  19. VringerE. TaitS.W.G. Mitochondria and cell death-associated inflammation.Cell Death Differ.202330230431210.1038/s41418‑022‑01094‑w36447047
     [Google Scholar]
  20. LeviS. RipamontiM. DardiM. CozziA. SantambrogioP. Mitochondrial ferritin: Its role in physiological and pathological conditions.Cells2021108196910.3390/cells1008196934440737
     [Google Scholar]
  21. WangP. CuiY. RenQ. YanB. ZhaoY. YuP. GaoG. ShiH. ChangS. ChangY.Z. Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis.Cell Death Dis.202112544710.1038/s41419‑021‑03725‑533953171
     [Google Scholar]
  22. WuW. ChangS. WuQ. XuZ. WangP. LiY. YuP. GaoG. ShiZ. DuanX. ChangY.Z. Mitochondrial ferritin protects the murine myocardium from acute exhaustive exercise injury.Cell Death Dis.2016711e247510.1038/cddis.2016.37227853170
     [Google Scholar]
  23. GuaraldoM. SantambrogioP. RovelliE. Di SavinoA. SaglioG. CittaroD. RoettoA. LeviS. Characterization of human mitochondrial ferritin promoter: Identification of transcription factors and evidences of epigenetic control.Sci. Rep.2016613343210.1038/srep3343227625068
     [Google Scholar]
  24. TsukadaJ. YoshidaY. KominatoY. AuronP.E. The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation.Cytokine201154161910.1016/j.cyto.2010.12.01921257317
     [Google Scholar]
  25. JiaoY. TongC.S.W. ZhaoL. ZhangY. NichollsJ.M. RainerT.H. Intraperitoneal versus intranasal administration of lipopolysaccharide in causing sepsis severity in a murine model: A preliminary comparison.Lab. Anim. Res.20244011810.1186/s42826‑024‑00205‑738741131
     [Google Scholar]
  26. HuangW. LouA. WangJ. WangY. ZhangW. LiJ. WangS. GengS. WangG. LiX. TMBIM1 ameliorates sepsis‐induced cardiac dysfunction by promoting Parkin‐mediated mitophagy.FASEB J.2025394e7039710.1096/fj.202402599RR39937566
     [Google Scholar]
  27. ChenX.S. CuiJ.R. MengX.L. WangS.H. WeiW. GaoY.L. ShouS.T. LiuY.C. ChaiY.F. Angiotensin-(1–7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways.J. Transl. Med.2023211210.1186/s12967‑022‑03842‑536593471
     [Google Scholar]
  28. QiuZ. ZhouK. QiQ. ChenW. Silencing fatty acid-binding protein 4 improved sepsis-induced myocardial dysfunction through anti-apoptotic and antioxidant effects by mammalian target of rapamycin signaling pathway.Cytojournal202522810.25259/Cytojournal_157_202439958886
     [Google Scholar]
  29. SrdićT. ĐuraševićS. LakićI. RužičićA. VujovićP. JevđovićT. DakićT. ĐorđevićJ. TostiT. GlumacS. TodorovićZ. JasnićN. From molecular mechanisms to clinical therapy: Understanding sepsis-induced multiple organ dysfunction.Int. J. Mol. Sci.20242514777010.3390/ijms2514777039063011
     [Google Scholar]
  30. YuX. GaoJ. ZhangC. Sepsis-induced cardiac dysfunction: Mitochondria and energy metabolism.Intensive Care Med. Exp.20251312010.1186/s40635‑025‑00728‑w39966268
     [Google Scholar]
  31. MollaceR. ScaranoF. BavaI. CarresiC. MaiuoloJ. TaverneseA. GliozziM. MusolinoV. MuscoliS. PalmaE. MuscoliC. SalveminiD. FedericiM. MacrìR. MollaceV. Modulation of the nitric oxide/cGMP pathway in cardiac contraction and relaxation: Potential role in heart failure treatment.Pharmacol. Res.202319610693110.1016/j.phrs.2023.10693137722519
     [Google Scholar]
  32. WolfertstetterS. HuettnerJ. SchlossmannJ. cGMP-dependent protein kinase inhibitors in health and disease.Pharmaceuticals20136226928610.3390/ph602026924275951
     [Google Scholar]
  33. CaiZ. WuC. XuY. CaiJ. ZhaoM. ZuL. The NO-cGMP-PKG axis in HFpEF: From pathological mechanisms to potential therapies.Aging Dis.2023141466210.14336/AD.2022.052336818566
     [Google Scholar]
  34. CostellM.H. AncellinN. BernardR.E. ZhaoS. UpsonJ.J. MorganL.A. ManiscalcoK. OlzinskiA.R. BallardV.L.T. HerryK. GrondinP. DodicN. MirguetO. BouillotA. GellibertF. CoatneyR.W. LeporeJ.J. JuckerB.M. JolivetteL.J. WilletteR.N. SchnackenbergC.G. BehmD.J. Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress.Front. Pharmacol.2012312810.3389/fphar.2012.0012822783192
     [Google Scholar]
  35. LiuD. QinH. GaoY. SunM. WangM. Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation.Pharmacol. Res.202420610725810.1016/j.phrs.2024.10725838909638
     [Google Scholar]
  36. ArosioP. LeviS. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage.Biochim. Biophys. Acta, Gen. Subj.20101800878379210.1016/j.bbagen.2010.02.00520176086
     [Google Scholar]
  37. ZhangJ. ChenX. HongJ. TangA. LiuY. XieN. NieG. YanX. LiangM. Biochemistry of mammalian ferritins in the regulation of cellular iron homeostasis and oxidative responses.Sci. China Life Sci.202164335236210.1007/s11427‑020‑1795‑432974854
     [Google Scholar]
  38. ZhangY. XinL. XiangM. ShangC. WangY. WangY. CuiX. LuY. The molecular mechanisms of ferroptosis and its role in cardiovascular disease.Biomed. Pharmacother.202214511242310.1016/j.biopha.2021.11242334800783
     [Google Scholar]
  39. MaccarinelliF. GammellaE. AspertiM. RegoniM. BiasiottoG. TurcoE. AltrudaF. LonardiS. CornaghiL. DonettiE. RecalcatiS. PoliM. FinazziD. ArosioP. CairoG. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity.J. Mol. Med.201492885986910.1007/s00109‑014‑1147‑024728422
     [Google Scholar]
  40. HaraY. YanatoriI. TanakaA. KishiF. LemastersJ.J. NishinaS. SasakiK. HinoK. Iron loss triggers mitophagy through induction of mitochondrial ferritin.EMBO Rep.20202111e5020210.15252/embr.20205020232975364
     [Google Scholar]
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Stimulation of Soluble Guanylyl Cyclase (sGC) by Cinaciguat Attenuates Sepsis-induced Cardiac Injury
Curr Mol Pharmacol 17, E18761429387280 (2024); https://doi.org/10.2174/0118761429387280250506114040
/content/journals/cmp/10.2174/0118761429387280250506114040
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  • Article Type:     Research Article
Keyword(s): Cinaciguat; CREB; FtMt; PRKG1; Sepsis-induced cardiac injury; sGC

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