title: Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin (Dox) could trigger a large amount of apoptotic cells in the myocardium, which leads to dilated cardiomyopathy and heart failure. S-propargyl-cysteine (SPRC), a producing agent of endogenous hydrogen sulfide (H2S), possesses cardioprotective efficacy. However, the specific effect and mechanism of SPRC in Dox-induced cardiotoxicity remain elusive. Given gp130 with its main downstream signaling molecule, signal transducer and activator of transcription 3 (STAT3), is involved in cardiac myocyte survival and growth; the present study was performed to elucidate whether SPRC counteracts Dox-induced cardiotoxicity, and if so, whether the gp130/STAT3 pathway is involved in this cardioprotective activity. SPRC stimulated the activation of STAT3 via gp130-mediated transduction tunnel in vitro and in vivo. In Dox-stimulated cardiotoxicity, SPRC enhanced cell viability, restored expression of gp130/STAT3-regulated downstream genes, inhibited apoptosis and oxidative stress, and antagonized mitochondrial dysfunction and intracellular Ca(2+) overload. Intriguingly, blockade of gp130/STAT3 signaling abrogated all these beneficial capacities of SPRC. Our findings present the first piece of evidence for the therapeutic properties of SPRC in alleviating Dox cardiotoxicity, which could be attributed to the activation of gp130-mediated STAT3 signaling. This will offer a novel molecular basis and therapeutic strategy of H2S donor for the treatment of heart failure.
authors.affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: S-Z
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: J-T
authors.initials: JT
authors.lastname: Kan
authors.affiliation: Department of Cardiovascular Surgery, Guangdong General Hospital, Guangzhou, Guangdong, China.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.|School of Pharmacy, Macau University of Science & Technology, Macau, China.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D066126:Cardiotoxicity / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; C556437:S-propargylcysteine; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D004317:Doxorubicin; D003545:Cysteine; D002118:Calcium; D006862:Hydrogen Sulfide