Sirt6 protects cardiomyocytes against doxorubicin-induced cardiotoxicity by inhibiting P53/Fas-dependent cell death and augmenting endogenous antioxidant defense mechanisms.

Sisi Wu,Li Fu,Xin Yan,Xiaoxiao Wang,Juanjuan Xin,Xue Li,Lingyu Li,Ruli Li,Mingming Tong,Jie Lan,Jiayi Xu,Wei Jiang,Hongying Chen,Kunyue Xue,He Li,Yao Wu,Xuemei Chen,Caili Zhuo,Yanjing Zhang

doi:10.1007/s10565-021-09649-2

Sisi Wu, Li Fu + Show 17 more

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https://doi.org/10.1007/s10565-021-09649-2

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Abstract

Sirt6, a class III NAD+-dependent deacetylase of the sirtuin family, is a highly specific H3 deacetylase and plays important roles in regulating cellular growth and death. The induction of oxidative stress and death is the critical mechanism involved in cardiomyocyte injury and cardiac dysfunction in doxorubicin-induced cardiotoxicity, but the regulatory role of Sirt6 in the fate of DOX-impaired cardiomyocytes is poorly understood. In the present study, we exposed Sirt6 heterozygous (Sirt6+/-) mice and their littermates as well as cultured neonatal rat cardiomyocytes to DOX, then investigated the role of Sirt6 in mitigating oxidative stress and cardiac injury in the DOX-treated myocardium. Sirt6 partial knockout or silencing worsened cardiac damage, remodeling, and oxidative stress injury in mice or cultured cardiomyocytes with DOX challenge. Cardiomyocytes infected with adenoviral constructs encoding Sirt6 showed reversal of this DOX-induced damage. Intriguingly, Sirt6 reduced oxidative stress injury by upregulating endogenous antioxidant levels, interacted with oxidative stress-stirred p53, and acted as a co-repressor of p53 in nuclei. Sirt6 was recruited by p53 to the promoter regions of the target genes Fas and FasL and further suppressed p53 transcription activity by reducing histone acetylation. Sirt6 inhibited Fas/FasL signaling and attenuated both Fas-FADD-caspase-8 apoptotic and Fas-RIP3 necrotic pathways. These results indicate that Sirt6 protects the heart against DOX-induced cardiotoxicity by upregulating endogenous antioxidants, as well as suppressing oxidative stress and cell death signaling pathways dependent on ROS-stirred p53 transcriptional activation, thus reducing Fas-FasL-mediated apoptosis and necrosis. •Sirt6 is significantly decreased in DOX-insulted mouse hearts and cardiomyocytes. •Sirt6 attenuates DOX-induced cardiac atrophy, dysfunction and oxidative stress. • Sirt6 reduces oxidative stress injury by upregulating endogenous antioxidants. • Sirt6 interacts with p53 as a co-repressor to suppress p53 transcriptional regulation and inhibits Fas-FasL-mediated apoptosis and necrosis downstream of p53.

Highlights

Doxorubicin (DOX) is a highly efficacious anticancer therapeutic drug but causes serious cardiotoxicity (Kalyanaraman et al 2020; Zhang et al 2009)
We confirmed that DOX treatment significantly increased both mFasL and Fas protein levels in the cellular membrane of neonatal rat cardiomyocytes (NRCMs), which were significantly augmented by Sirt6 silencing but reduced by Sirt6 overexpression (Fig. 6f)
Cardiomyocyte apoptosis and necrosis could be a fundamental part of the myocardial process that initiates or aggravates heart failure (Prathumsap et al 2020; Zhang et al 2009)

Summary

Introduction

Doxorubicin (DOX) is a highly efficacious anticancer therapeutic drug but causes serious cardiotoxicity (Kalyanaraman et al 2020; Zhang et al 2009). Cardiomyocyte death due to apoptosis and necrosis is a critical mechanism of DOX-induced cardiotoxicity (Kalyanaraman et al 2020; Zhang et al 2009). Free radical-induced oxidative stresses play a pivotal role in DOX-induced cardiotoxicity, and other contributors including abnormalities of calcium handling, adrenergic impairment, and selective inhibition of cardiomyocyte-specific gene expression participate in its pathogenesis (Prathumsap et al 2020; Kumari et al 2020). Located in the nucleus, is a stressresponsive protein deacetylase and mono-ADP ribosyltransferase enzyme that plays a leading role in regulating genomic stability, cell metabolism, inflammation, stress response and aging (Saiyang et al.2020; Poulose et al 2015; Hall et al 2013). Ran et al observed that Sirt was recruited to the promoter of Bcl2-associated X, where it deacetylated H3K9 and suppressed its promoter activity to reduce Bax mRNA expression, inhibited tumor cell apoptosis, thereby suggesting that Sirt can directly regulate cell death by interacting with apoptosis-related genes (Ran et al 2016)

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