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The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.

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As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin (Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Dox-induced cardiomyocytes apoptosis in a dose-dependent manner in vitro . Administration with Isor (30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro . Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

Background and Purpose Activation of PKC‐ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC‐ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)‐trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1‐PKC‐ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. Experimental Approach Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague‐Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC‐ζ was investigated by co‐immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad‐sirtuin1 transfection. A model of cardiac hypertrophy in Sprague‐Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo. Key Results Overexpression of PKC‐ζ led to cardiac hypertrophy and increased activity of NF‐κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC‐ζ, hindered its binding to phosphoinositide‐dependent kinase 1 and inhibited PKC‐ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC‐ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy. Conclusions and Implications Sirtuin1 is an endogenous negative regulator for PKC‐ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1‐PKC‐ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.