Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction.
Siying LiWenjuan WangTing NiuHui WangBin LiLei ShaoYimu LaiHuanjie LiJoseph S JanickiXing Li WangDongqi TangTaixing CuiPublished in: Oxidative medicine and cellular longevity (2014)
The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2(-/-)) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
Keyphrases
- oxidative stress
- diabetic rats
- high glucose
- drug induced
- induced apoptosis
- dna damage
- cell death
- ischemia reperfusion injury
- endoplasmic reticulum stress
- endothelial cells
- heart failure
- signaling pathway
- drug delivery
- metabolic syndrome
- cell proliferation
- heat shock
- intensive care unit
- hepatitis b virus
- dna methylation
- toll like receptor
- small molecule
- adipose tissue
- liver failure
- mesenchymal stem cells
- skeletal muscle
- stress induced
- mass spectrometry
- acute respiratory distress syndrome