Abstract 2055: Regulatory Role of Hypoxia-Inducible Factor-1α and Redox-Regulated Transcription Factor in Doxorubicin Cardiotoxicity
Background: Hypoxia-inducible factor-1α(HIF-1α) that correlates with angiogenesis is a transcription factor that plays important roles in cellular response to hypoxia in various cancers. However, recently, it has been shown that HIFs mediate cytokine signaling in the ventricular myocardium. The present study investigated involvement of angiogenesis and oxidative stress with the cardiotoxicity of doxorubicin (DOX), and effects of the peroxisome proliferator-activated receptor-α activator, fenofibrate, and antioxidant, superoxide dismutase (SOD), on the cardiotoxicity.
Methods and Results: To test the hypothesis that HIF-1α plays a role in the DOX-induced cardiac failure, male C57/BL mice at 8 weeks of age were injected intraperitoneally with DOX at 15 mg/kg. Fenofibrate at 50 and 200 mg/kg and SOD at 4,000 and 20,000 U/kg body weight per day were orally given after injection of DOX. Four days after the DOX injection, its effects on heart were examined. Echocardiography revealed the thinning of the interventricular septum and the reduction of LV contractile function in DOX-injected mice. Treatment with fenofibrate or SOD prevented these changes. Biochemical assays showed that the ratio of reduced to oxidized glutathione was decreased whereas the concentrations of hexanoyl-lysine and 3-nitrotyrosine were increased in the left ventricle of DOX-injected mice; these changes were also prevented by treatment with fenofibrate or SOD. The mRNA expression of HIF-1α and the angiogenic cytokine vascular endothelial growth factor (VEGF), and the DNA binding activity of the nuclear factor (NF)-κB in the left ventricle were increased in DOX-injected mice. Treatment with fenofibrate suppressed the increase in the binding activity of NF-κ B whereas treatment with SOD prevented these changes of HIF-1α, VEGF, and NF-κB.
Conclusions: Both fenofibrate and SOD prevented cardiac dysfunction induced by DOX in murine models through normalization of oxidative stress and dysregulation of angiogenesis. The involvement of NF-κB was found in both of the prevention models, but that of HIF-1α and VEGF was only confirmed in the animals administered SOD.