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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, 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 triggered STAT3 via gp130 in both cultured cardiomyocytes and rodent hearts, determined using siRNA transfection, western blot, co-immunoprecipitation, or/and immunocytochemical analysis.
SPRC stimulated the activation of STAT3 via gp130-mediated transduction tunnel in vitro and in vivo. In Dox-stimulated cardiotoxicity, SPRC enhanced cell viability, reduced lactate dehydrogenase (LDH) release, 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 by SC144, a novel gp130/STAT3 pathway inhibitor, 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-medaited STAT3 signaling. This will offer a novel molecular basis and therapeutic strategy of an H2S donor for the treatment of heart failure.