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Abstract

Introduction

The present study aimed to examine the functions of heat shock protein 90 (HSP90), NF-κB, C3, and C5a in cardioprotective effects induced by vericiguat in mice.

Methods

Male mice were randomly assigned to six groups: sham, ischemia/ reperfusion (I/R), vericiguat preconditioning (VPre), VPre + HSP90 inhibitor geldanamycin (GA), vericiguat postconditioning (VPost), and VPost + GA. An experimental mouse model of I/R was established in mice through surgery and treatments with vericiguat and GA. The following parameters were assessed: myocardial infarct size; cardiomyocyte apoptosis; cTnI, CK-MB, and LDH serum levels, protein expression levels of Bcl-2, Bax, HSP90, NF-κB, and complement components C3 and C5a, and mRNA expression levels of IL-1β, TNF-α, and ICAM-1.

Results

Vericiguat significantly attenuated the myocardial infarct size induced by I/R injury; suppressed cardiomyocyte apoptosis; reduced serum levels of myocardial markers (CK-MB, LDH, and cTnI); decreased C5a, and C3 levels, NF-κB signaling, and expression of inflammatory cytokine (ICAM-1,TNF-α, and IL-1β); and enhanced HSP90 and Bcl-2 expression levels. However, GA reversed these effects.

Discussion

The study contributes to the investigation of the crosstalk between HSP90 and complement in the protective effects of vericiguat on myocardial I/R injury. However, further in-depth research is needed to explore the underlying mechanisms of vericiguat's cardioprotective effects against myocardial I/R injury.

Conclusion

HSP90 plays a crucial role in the cardioprotective effects of vericiguat, providing new insights into its mechanisms of action.

© 2025 Bentham Science Publishers
© 2025 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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2025-11-19
2025-11-29

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References

  1. Thygesen K. Alpert J.S. White H.D. Universal definition of myocardial infarction. J. Am. Coll. Cardiol. 2007 50 22 2173 2195 10.1016/j.jacc.2007.09.011 18036459
    [Google Scholar]
  2. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015 385 9963 117 171 10.1016/S0140‑6736(14)61682‑2 25530442
    [Google Scholar]
  3. Davidson S.M. Ferdinandy P. Andreadou I. Multitarget strategies to reduce myocardial ischemia/reperfusion injury. J. Am. Coll. Cardiol. 2019 73 1 89 99 10.1016/j.jacc.2018.09.086 30621955
    [Google Scholar]
  4. Cai Y. Zhang B. Shalamu A. Gao T. Ge J. Soluble guanylate cyclase (sGC) stimulator vericiguat alleviates myocardial ischemia-reperfusion injury by improving microcirculation. Ann. Transl. Med. 2022 10 12 662 10.21037/atm‑22‑2583 35845490
    [Google Scholar]
  5. Armstrong P.W. Pieske B. Anstrom K.J. Vericiguat in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 2020 382 20 1883 1893 10.1056/NEJMoa1915928 32222134
    [Google Scholar]
  6. Saldarriaga C. Atar D. Stebbins A. Vericiguat in patients with coronary artery disease and heart failure with reduced ejection fraction. Eur. J. Heart Fail. 2022 24 5 782 790 10.1002/ejhf.2468 35239245
    [Google Scholar]
  7. Zhu W. Ben Y. Shen Y. Liu W. Vericiguat protects against cardiac damage in a pig model of ischemia/reperfusion. PLoS One 2023 18 12 0295566 10.1371/journal.pone.0295566 38134018
    [Google Scholar]
  8. Panagiotou A. Trendelenburg M. Osthoff M. The lectin pathway of complement in myocardial ischemia/reperfusion injury—Review of its significance and the potential impact of therapeutic interference by C1 Esterase inhibitor. Front. Immunol. 2018 9 1151 10.3389/fimmu.2018.01151 29910807
    [Google Scholar]
  9. Vogel C.W. The role of complement in myocardial infarction reperfusion injury: An underappreciated therapeutic target. Front. Cell Dev. Biol. 2020 8 606407 10.3389/fcell.2020.606407 33425913
    [Google Scholar]
  10. Han H. Dong P. Liu K. The role of NF-κB in myocardial ischemia/reperfusion injury. Curr. Protein Pept. Sci. 2022 23 8 535 547 10.2174/1389203723666220817085941 35980051
    [Google Scholar]
  11. Pluijmert N.J. Atsma D.E. Quax P.H.A. Post-ischemic myocardial inflammatory response: A complex and dynamic process susceptible to immunomodulatory therapies. Front. Cardiovasc. Med. 2021 8 647785 10.3389/fcvm.2021.647785 33996944
    [Google Scholar]
  12. Zhang X.Y. Liu Y. He T. Anaphylatoxin C5a induces inflammation and reduces insulin sensitivity by activating TLR4/NF-kB/PI3K signaling pathway in 3T3-L1 adipocytes. Biomed. Pharmacother. 2018 103 955 964 10.1016/j.biopha.2018.04.057 29710512
    [Google Scholar]
  13. Aceros H. Der Sarkissian S. Borie M. Stevens L.M. Mansour S. Noiseux N. Celastrol-type HSP90 modulators allow for potent cardioprotective effects. Life Sci. 2019 227 8 19 10.1016/j.lfs.2019.04.025 30986447
    [Google Scholar]
  14. Peng C. Zhao F. Li H. Li L. Yang Y. Liu F. HSP90 mediates the connection of multiple programmed cell death in diseases. Cell Death Dis. 2022 13 11 929 10.1038/s41419‑022‑05373‑9 36335088
    [Google Scholar]
  15. Amour J. Brzezinska A.K. Weihrauch D. Role of heat shock protein 90 and endothelial nitric oxide synthase during early anesthetic and ischemic preconditioning. Anesthesiology 2009 110 2 317 325 10.1097/ALN.0b013e3181942cb4 19194158
    [Google Scholar]
  16. Vladic N. Ge Z.D. Leucker T. Decreased tetra-hydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 2011 301 5 H2130 H2139 10.1152/ajpheart.01078.2010 21908789
    [Google Scholar]
  17. Wang D.X. Huang Z. Li Q.J. Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation. Acta Cir. Bras. 2020 35 1 202000105 10.1590/s0102‑865020200010000005 32215465
    [Google Scholar]
  18. He S.T. Wang D.X. Meng J.J. HSP90-mediates liraglutide preconditioning-induced cardioprotection by inhibiting C5a and NF-κB. J. Invest. Surg. 2022 35 5 1012 1020 10.1080/08941939.2021.1989729 34670452
    [Google Scholar]
  19. Wang D. He S. Zhong G. Meng J. Bi Q. Tu R. Effects of heat shock protein 90 on complement activation in myocardial ischemia/reperfusion injury after pioglitazone preconditioning. Adv. Clin. Exp. Med. 2023 32 12 1401 1412 10.17219/acem/162578 37140018
    [Google Scholar]
  20. Chen T. Kong B. Shuai W. Gong Y. Zhang J. Huang H. Vericiguat alleviates ventricular remodeling and arrhythmias in mouse models of myocardial infarction via CaMKII signaling. Life Sci. 2023 334 122184 10.1016/j.lfs.2023.122184 37866806
    [Google Scholar]
  21. Janssen W. Schwarz T. Bütehorn U. Pharmacokinetics and mass balance of vericiguat in rats and dogs and distribution in rats. Xenobiotica 2022 52 5 453 462 10.1080/00498254.2022.2082899 35616579
    [Google Scholar]
  22. Zhong G.Q. Tu R.H. Zeng Z.Y. Novel functional role of heat shock protein 90 in protein kinase C-mediated ischemic postconditioning. J. Surg. Res. 2014 189 2 198 206 10.1016/j.jss.2014.01.038 24742623
    [Google Scholar]
  23. Singh C. Roy-Chowdhuri S. Quantitative real-time PCR: Recent advances. Methods Mol. Biol. 2016 1392 161 176 10.1007/978‑1‑4939‑3360‑0_15 26843055
    [Google Scholar]
  24. Livak K.J. Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)). Method. Methods 2001 25 4 402 408 10.1006/meth.2001.1262 11846609
    [Google Scholar]
  25. Zhang X.Y. Huang Z. Li Q.J. Role of HSP90 in suppressing TLR4-mediated inflammation in ischemic postconditioning. Clin. Hemorheol. Microcirc. 2020 76 1 51 62 10.3233/CH‑200840 32651307
    [Google Scholar]
  26. Eefting F. Rensing B. Wigman J. Role of apoptosis in reperfusion injury. Cardiovasc. Res. 2004 61 3 414 426 10.1016/j.cardiores.2003.12.023 14962473
    [Google Scholar]
  27. Wang H. Pang W. Xu X. You B. Zhang C. Li D. Cryptotanshinone attenuates ischemia/reperfusion-induced apoptosis in myocardium by upregulating MAPK3. J. Cardiovasc. Pharmacol. 2021 77 3 370 377 10.1097/FJC.0000000000000971 33662979
    [Google Scholar]
  28. Saraste A. Pulkki K. Kallajoki M. Henriksen K. Parvinen M. Voipio-Pulkki L.M. Apoptosis in human acute myocardial infarction. Circulation 1997 95 2 320 323 10.1161/01.CIR.95.2.320 9008443
    [Google Scholar]
  29. Li J. Wang S. Huang S. Shao W. Zhang J. Remifentanil anesthesia on the expression of apoptosis-related proteins Bcl-2 and Bax in rat myocardial cells with ischemia-reperfusion injury. Cell. Mol. Biol. 2022 67 5 96 103 10.14715/cmb/2021.67.5.13 35818266
    [Google Scholar]
  30. Korshunova A. Blagonravov M. Neborak E. BCL2-regulated apoptotic process in myocardial ischemia-reperfusion injury(Review). Int. J. Mol. Med. 2020 47 1 23 36 10.3892/ijmm.2020.4781 33155658
    [Google Scholar]
  31. Zhu X. Li S. Huang C. Huang G. Xu J. LncRNA CRNDE inhibits cardiomyocytes apoptosis by YAP1 in myocardial ischaemia/reperfusion injury. Autoimmunity 2021 54 4 204 212 10.1080/08916934.2021.1913580 33988471
    [Google Scholar]
  32. Cohen-Saidon C. Carmi I. Keren A. Razin E. Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90β. Blood 2006 107 4 1413 1420 10.1182/blood‑2005‑07‑2648 16166581
    [Google Scholar]
  33. Yasojima K. Schwab C. McGeer E.G. McGeer P.L. Human heart generates complement proteins that are upregulated and activated after myocardial infarction. Circ. Res. 1998 83 8 860 869 10.1161/01.RES.83.8.860 9776733
    [Google Scholar]
  34. Imanaka-Yoshida K. Inflammation in myocardial disease: From myocarditis to dilated cardiomyopathy. Pathol. Int. 2020 70 1 1 11 10.1111/pin.12868 31691489
    [Google Scholar]
  35. Salloum F.N. Das A. Samidurai A. Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: Role of hydrogen sulfide. Am. J. Physiol. Heart Circ. Physiol. 2012 302 6 H1347 H1354 10.1152/ajpheart.00544.2011 22268103
    [Google Scholar]
  36. Mace E.H. Kimlinger M.J. Billings F.T. Targeting soluble guanylyl cyclase during ischemia and reperfusion. Cells 2023 12 14 1903 10.3390/cells12141903 37508567
    [Google Scholar]
  37. Yao Y. Li F. Zhang M. Targeting CaMKII-δ9 ameliorates cardiac ischemia/reperfusion injury by inhibiting myocardial inflammation. Circ. Res. 2022 130 6 887 903 10.1161/CIRCRESAHA.121.319478 35152717
    [Google Scholar]
  38. Nitkiewicz J. Borjabad A. Morgello S. HIV induces expression of complement component C3 in astrocytes by NF-κB-dependent activation of interleukin-6 synthesis. J. Neuroinflammation 2017 14 1 23 10.1186/s12974‑017‑0794‑9 28122624
    [Google Scholar]
  39. Liu M. Wang H. Zhang J. NF-κB signaling pathway-enhanced complement activation mediates renal injury in trichloroethylene-sensitized mice. J. Immunotoxicol. 2018 15 1 63 72 10.1080/1547691X.2017.1420712 29534626
    [Google Scholar]
  40. Oliveira J.B. Soares A.A.S.M. Sposito A.C. Inflammatory response during myocardial infarction. Adv. Clin. Chem. 2018 84 39 79 10.1016/bs.acc.2017.12.002 29478516
    [Google Scholar]
  41. Tang B. Ma J. Ha X. Zhang Y. Xing Y. Tumor necrosis factor-alpha upregulated PHLPP1 through activating nuclear factor-kappa B during myocardial ischemia/reperfusion. Life Sci. 2018 207 355 363 10.1016/j.lfs.2018.06.023 29940243
    [Google Scholar]
  42. Taipale M. Jarosz D.F. Lindquist S. HSP90 at the hub of protein homeostasis: Emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 2010 11 7 515 528 10.1038/nrm2918 20531426
    [Google Scholar]
  43. Stuehr D.J. Misra S. Dai Y. Ghosh A. Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase. J. Biol. Chem. 2021 296 100336 10.1016/j.jbc.2021.100336 33508317
    [Google Scholar]
  44. Papapetropoulos A. Zhou Z. Gerassimou C. Interaction between the 90-kDa heat shock protein and soluble guanylyl cyclase: Physiological significance and mapping of the domains mediating binding. Mol. Pharmacol. 2005 68 4 1133 1141 10.1124/mol.105.012682 16024662
    [Google Scholar]
  45. Venema R.C. Venema V.J. Ju H. Novel complexes of guanylate cyclase with heat shock protein 90 and nitric oxide synthase. Am. J. Physiol. Heart Circ. Physiol. 2003 285 2 H669 H678 10.1152/ajpheart.01025.2002 12676772
    [Google Scholar]
  46. Nedvetsky P.I. Meurer S. Opitz N. Nedvetskaya T.Y. Müller H. Schmidt H.H.H.W. Heat shock protein 90 regulates stabilization rather than activation of soluble guanylate cyclase. FEBS Lett. 2008 582 2 327 331 10.1016/j.febslet.2007.12.025 18155168
    [Google Scholar]
  47. Cheng X.F. He S.T. Zhong G.Q. Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation. BMC Cardiovasc. Disord. 2023 23 1 58 10.1186/s12872‑023‑03043‑y 36726083
    [Google Scholar]
  48. Wang M. Sun G. Du Y. Myricitrin protects cardiomyocytes from hypoxia/reoxygenation injury: Involvement of heat shock protein 90. Front. Pharmacol. 2017 8 353 10.3389/fphar.2017.00353 28642708
    [Google Scholar]
  49. Sreedhar A.S. Mihály K. Pató B. Hsp90 inhibition accelerates cell lysis. Anti-Hsp90 ribozyme reveals a complex mechanism of Hsp90 inhibitors involving both superoxide- and Hsp90-dependent events. J. Biol. Chem. 2003 278 37 35231 35240 10.1074/jbc.M301371200 12842893
    [Google Scholar]
  50. Sreedhar A.S. Nardai G. Csermely P. Enhancement of complement-induced cell lysis: A novel mechanism for the anticancer effects of Hsp90 inhibitors. Immunol. Lett. 2004 92 1-2 157 161 10.1016/j.imlet.2003.11.025 15081540
    [Google Scholar]
  51. Tu R.H. Wang D.X. Zhong G.Q. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB. Open Med. 2021 16 1 1552 1563 10.1515/med‑2021‑0340 34722891
    [Google Scholar]
  52. Stebbins C.E. Russo A.A. Schneider C. Rosen N. Hartl F.U. Pavletich N.P. Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent. Cell 1997 89 2 239 250 10.1016/S0092‑8674(00)80203‑2 9108479
    [Google Scholar]
  53. Prodromou C. Roe S.M. O’Brien R. Ladbury J.E. Piper P.W. Pearl L.H. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 1997 90 1 65 75 10.1016/S0092‑8674(00)80314‑1 9230303
    [Google Scholar]
  54. Sun X. Bristol J.A. Iwahori S. Hsp90 inhibitor 17-DMAG decreases expression of conserved herpesvirus protein kinases and reduces virus production in Epstein-Barr virus-infected cells. J. Virol. 2013 87 18 10126 10138 10.1128/JVI.01671‑13 23843639
    [Google Scholar]
  55. Mellatyar H. Talaei S. Nejati-Koshki K. Akbarzadeh A. Targeting HSP90 gene expression with 17-DMAG nanoparticles in breast cancer cells. Asian Pac. J. Cancer Prev. 2016 17 5 2453 2457 27268613
    [Google Scholar]
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Therapeutic Potential of Vericiguat in Myocardial Ischemia/ Reperfusion Injury: Crosstalk between Heat Shock Protein 90 and Complement Activation
Bentham Science Publishers ; https://doi.org/10.2174/0115665240406330250911142757
/content/journals/cmm/10.2174/0115665240406330250911142757
/content/journals/cmm/10.2174/0115665240406330250911142757
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  • Article Type:     Research Article
Keywords: Vericiguat ; inflammation ; myocardial ischemia/reperfusion injury ; apoptosis ; HSP90 ; complement ; mice

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