SIRT1 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the Oxidative Stress and p38MAPK Pathways

Abstract

Background: SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro. Methods: We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results: SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes. Conclusions: These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

Sirtuins, aging, and cardiovascular risks

“…Activation of SIRT1 not only suppresses apoptosis but also balances oxidative stress in the heart, while absence of SIRT1 triggers chronic inflammation, oxidative stress, and cell cycle arrest (Gu et al 2013). Further, Ruan et al (2015) demonstrated that SIRT1 expression was downregulated in doxorubicin-induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis, and interestingly, SIRT1 is involved in the protection of the heart from doxorubicin-induced pathway, partly through the inhibition of the p38 MAPK pathway.…”

“…In addition, several sirtuins play additional roles in metabolic homeostasis (Choi and Mostoslavsky 2014). Based on their enzymatic activities, sirtuins can also play a pivotal role in oxidative stress modulation (Conti et al 2015;Li et al 2015;Zhang et al 2015). Sirtuins are intimately linked to the cellular response to oxidative stress (Merksamer et al 2013); they might be activated during redox stress and may modulate crucial responses, including the adaptation to hypoxia and ameliorating ROS-induced pathologies (Webster et al 2012).…”

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

“…reporting that SIRT1 could promote cardiomyocyte cell survival following acute doxorubicininduced oxidative burden by attenuating ROS production (152). Thus there may be an optimal activity level and time-specific application of sirtuin function to attenuate contributing factors of vascular aging.…”

Qiliqiangxin improves oxidized low-density lipoprotein-induced human coronary artery endothelial cells injury

“…The excessive caspase-3 activity induced cell apoptosis in various types of cells [11][12][13]. Ox-LDL induced cells apoptosis via eliciting the caspase-3 activity [14][15][16][17][18].…”