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 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.

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…In an adjuvant-induced arthritis model, SPRC suppressed joint swelling and downregulated the production of multiple inflammatory mediators in the joint (Wu et al, 2016d). SPRC was also efficacious in a nonalcoholic liver disease model in mice (Li et al, 2016) and in a doxorubicin model of myocardial dysfunction in rats (Wu et al, 2016b). Consistently with the bell-shaped dose-response of H 2 S in cancer (reviewed in Szabo, 2016), higher doses of SPRC exerted inhibitory effects on tumor growth in tumor-bearing mice in vivo; for example, at 100 (mg/kg)/day, SPRC induced an approximately 50% inhibitory effect of the growth of gastric cancer cells implanted into nude mice (Ma et al, 2011).…”

“…The molecular and biochemical pathways associated with the effects of SPRC are multiple; they include the stimulation of Akt phosphorylation (Yang et al, 2015;Li et al, 2016), activation of the antioxidant "master switch" Nrf2 (Yang et al, 2015;Wu et al, 2016d), upregulation of CSE mRNA, CSE protein and CSE activity (Wu et al, 2009;Ma et al, 2011;Huang et al, 2013;Yang et al, 2015;Li et al, 2016), inhibition of nuclear factor-kB activation (Pan et al, 2012), vascular endothelial growth factor receptor activation followed by STAT3 activation (Kan et al, 2014;Wu et al, 2016d), upregulation of cellular antioxidant systems (superoxide dismutase, catalase, glutathione peroxidase, heme oxygenase-1) (Wu et al, 2016b;Li et al, 2016), elevation of intracellular glutathione levels (Wu et al, 2016b), reduction of cellular ROS levels (Pan et al, 2012;Li et al, 2016), and improvement of cellular calcium handling (Liang et al, 2015). In the context of cytotoxic effects of SPRC in cancer cells, at higher concentrations/doses, the compound was also found to increase bcl-2-like protein 4 and p53 expression (Ma et al, 2011).…”

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

“…This might also affect cardiac fate. For example, doxorubicin reduces cardiomyocyte STAT3 expression, and overexpression of gp130‐STAT3 signalling has been shown to protect against doxorubicin‐induced cardiotoxicity …”

Hydrogen Sulfide as a Potential Alternative for the Treatment of Myocardial Fibrosis

“…Although fibrosis is an essential process for the restoration and maintenance of organ integrity after injury or stress via the timely deposition of the extracellular matrix (ECM), the aberrant accumulation of stiff and disorganized ECM progressively disrupts tissue function and can ultimately cause organ failure [1][2][3][4][5]. Myocardial fibrosis is a hallmark feature of heart failure and is associated with hypertension, myocardial infarction (MI), and pathological hypertrophy followed by injury and stress [1,2].…”