Resveratrol protects against doxorubicin‐induced cardiotoxicity in aged hearts through the SIRT1‐USP7 axis

Abstract

Key pointsr Doxorubicin induced functional deteriorations and elevations of USP7-related apoptotic/catabolic signalling in the senescent heart r Resveratrol protects against doxorubicin-induced alterations through the restoration of SIRT1 deacetylase activity Abstract A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural anti-oxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of sirtuin 1 (SIRT1) deacetylase activity, and attenuation of the catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (aged 2 months) and old (aged 10 months) senescence-accelerated mice prone 8 (SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8. These doxorubicin-induced alterations were prevented by resveratrol, whereas the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increases in acetylation of Foxo1 and transactivation of MuRF-1, whereas these mitigations were not found after treatment with SIRT1 inhibitors. However, the protein contents of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentation of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in hearts from aged animals, whereas these reductions were diminished by combined treatment with SIRT1 inhibitors. These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in aged hearts through the restoration of SIRT1 activity to attenuate USP7-related catabolic/pro-apoptotic signalling. AbbreviationsAMPK, AMP-activated protein kinase; DR, doxorubicin + resveratrol; DRE, doxorubicin + resveratrol + EX527; DRS, doxorubicin + resveratrol + sirtinol; DV, doxorubicin and vehicle; EF, ejection fraction; FS, fractional shortening; LVEDD, left ventricle end-diastolic dimension; LVESD, left ventricle end-systolic dimension; SAMP8, senescence-accelerated mice prone 8; SC, saline control; SIRT1, sirtuin 1; TBST, Tris-buffered saline with 0.1% Tween 20; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling.

Resveratrol Reverses Functional Chagas Heart Disease in Mice

“…These results suggest a SIRT1-independent effect of resveratrol, and in fact treatment of infected mice with resveratrol plus EX527, an specific SIRT1 inhibitor used as previously described [37], was not able to reverse the significant benefits of resveratrol on ECG abnormalities (S7 Fig). Together, these data support the notion that AMPK, but not SIRT1, is activated in response to resveratrol in CCC.…”

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

“…Additionally, resveratrol, a SIRT 1 activator, is known to possess many beneficial biological activities. For instance, resveratrol can ameliorate doxorubicin-induced cardiotoxicity in aged hearts through restoring the SIRT1 activity, thus attenuating the USP7-related catabolic/ pro-apoptotic signaling [42]. Consequently, it can be easily speculated that TQ may exert its cardioprotective effect through activation of the SIRT 1 signaling pathway.…”

Resveratrol, a polyphenol phytoalexin, protects against doxorubicin‐induced cardiotoxicity

“…Taken together, it is concluded that HO‐1 plays a core role for protective action of resveratrol in doxorubicin‐induced cardiomyocytes apoptosis . Furthermore, it has been reported that resveratrol ameliorates doxorubicin‐induced apoptosis in cardiomyocytes through the restoration of SIRT1 activity, which decreases the level of acetylated p53 and p53‐dependent transcription of Bax .…”

“…Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent doxorubicin‐induced cardiotoxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro . It is noteworthy that the cardioprotective effect of resveratrol is associated with reduced oxidative stress, inhibited apoptosis and modulated autophagy process . This article discusses the protective effect of resveratrol in doxorubicin‐induced cardiotoxicity.…”

“…In addition, resveratrol can protect the heart against ischaemia‐reperfusion injury , improve endothelial function and prevent platelet aggregation . Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent doxorubicin‐induced cardiotoxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro . It is noteworthy that the cardioprotective effect of resveratrol is associated with reduced oxidative stress, inhibited apoptosis and modulated autophagy process .…”