Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity.

J Wu,Y-Z Zhu,S-Y Chen,Z-J Wang,S-Z Lin,J-T Kan,W Guo

doi:10.1038/cddis.2016.209

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 Ca2+ 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.

Highlights

The fundamental role for gp130-dependent pathway in heart failure has been elucidated using mice that harbor a ventricular-restricted knockout of the gp130.2 By contrast, activation of gp[130] promotes cardiomyocyte survival by inhibiting apoptosis.[1]
It has been established that the activated JAK1 or Janus kinase 2 (JAK2) phosphorylate gp[130], which serves as the docking receptor for signal transducer and activator of transcription 3 (STAT3).25 To investigate whether SPRC affects the recruitment of STAT3 to gp[130], we performed co-immunoprecipitation (Co-IP) assay
The STAT3 activation by SPRC was blunted by SC144 (Po0.01; Figure 1e), which could bind to gp[130], induce gp[130] phosphorylation and deglycosylation, and eventually abrogate STAT3 phosphorylation and nuclear translocation.[8]

Summary

Introduction

The fundamental role for gp130-dependent pathway in heart failure has been elucidated using mice that harbor a ventricular-restricted knockout of the gp130.2 By contrast, activation of gp[130] promotes cardiomyocyte survival by inhibiting apoptosis.[1]. The molecular mechanism involved in Doxinduced cardiotoxicity has been proposed to account for increasing reactive oxygen species (ROS) production, caspase activation, altered calcium handling and mitochondrial injury.[16,17] It was demonstrated that transgenic mice with cardiac-specific overexpression of STAT3 gene are protected against Dox-induced cardiomyopathy.[18] understanding how STAT3 activation can be modulated would provide new opportunities to develop effective therapeutics for Dox cardiotoxicity. SPRC promotes the activity of cystathionine-γ-lyase (CSE, a metabolic enzyme producing endogenous H2S) and augments H2S level in mammalian plasma and tissues.[20] Our previous studies confirmed that SPRC exerts extensive protective effects on cardiovascular diseases via anti-oxidative, anti-inflammatory, and proangiogenic mechanisms.[20,21,22,23] the definite role and mechanism of SPRC in Dox-induced cardiotoxicity are not well established. Because gp130-mediated STAT3 activation plays a fundamental role in cardioprotection, the modulation of gp130/STAT3 signaling by SPRC was delineated in both cultured cardiomyocytes and mouse hearts

Methods

Results

Conclusion