TAK1 activates AMPK-dependent cell death pathway in hydrogen peroxide-treated cardiomyocytes, inhibited by heat shock protein-70

The aim of this current study is to investigate the potential role of AMP-activated protein kinase (AMPK) in hydrogen peroxide (H 2 O 2 )-induced cardiomyocyte death, and focused on the signaling mechanisms of AMPK activation by H 2 O 2 . We observed a significant AMPK activation in H 2 O 2 -treated cardiomyocytes (both primary cells and H9c2 line). Inhibition of AMPK by its inhibitor or RNAi-reduced H 2 O 2 -induced cardiomyocyte death. We here proposed that transforming growth factor-β-activating kinase 1 (TAK1) might be the upstream kinase for AMPK activation by H 2 O 2 . H 2 O 2 -induced TAK1 activation, which recruited and activated AMPK. TAK1 inhibitor significantly suppressed H 2 O 2 -induced AMPK activation and following cardiomyocyte death, while over-expression of TAK1-facilitated AMPK activation and aggregated cardiomyocyte death. Importantly, heat shock protein-70 (HSP-70)-reduced H 2 O 2 -induced reactive oxygen species (ROS) accumulation, the TAK1/AMPK activation and cardiomyocyte death. In conclusion, we here suggest that TAK1 activates AMPK-dependent cell death pathway in H 2 O 2 -treated cardiomyocytes, and HSP-70 inhibits the signaling pathway by reducing ROS content.