Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1 R upregulation are required for doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence suggests that angiotensin receptor blockers (ARBs) have cardioprotective effects in DOX-induced cardiomyopathy. However, the detailed mechanisms underlying the action of ARBs on the prevention of DOX-induced cardiomyocyte cell death have yet to be investigated. Our results showed that angiotensin II receptor type I (AT1 R) plays a critical role in DOX-induced cardiomyocyte apoptosis. We found that MAPK signaling pathways, especially ERK1/2, participated in modulating AT1 R gene expression through DOX-induced mitochondrial ROS release. These results showed that several potential heat shock binding elements (HSE), which can be recognized by heat shock factors (HSFs), located at the AT1 R promoter region. HSF2 markedly translocated from the cytoplasm to the nucleus when cardiomyocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX-induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK-mediated HSF2 nuclear translocation and AT1 R upregulation causing DOX-damaged heart failure in vitro and in vivo.