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

Abstract

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.

• Authors: Chih-Yang Huang, Jia-Yi Chen, Chia-Hua Kuo, Pei-Ying Pai, Tsung-Jung Ho, Tung-Sheng Chen, Fu-Jen Tsai, Vijaya V Padma, Wei-Wen Kuo, Chih-Yang Huang
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 233 Issue 1 Pg. 463-475 (Jan 2018) ISSN: 1097-4652 [Electronic] United States
• PMID: 28295305 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Antibiotics, Antineoplastic
• Heat-Shock Proteins
• Hsf2 protein, rat
• Reactive Oxygen Species
• Receptor, Angiotensin, Type 1
• Transcription Factors
• Doxorubicin
• Mapk1 protein, rat
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Active Transport, Cell Nucleus
• Animals
• Antibiotics, Antineoplastic
• Apoptosis
• Binding Sites
• Cardiotoxicity
• Cell Line
• Disease Models, Animal
• Doxorubicin
• Enzyme Activation
• Heart Diseases (chemically induced, enzymology, genetics, pathology)
• Heat-Shock Proteins (metabolism)
• Mitochondria, Heart (enzymology, pathology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Myocytes, Cardiac (enzymology, pathology)
• Promoter Regions, Genetic
• RNA Interference
• Rats, Inbred WKY
• Reactive Oxygen Species (metabolism)
• Receptor, Angiotensin, Type 1 (genetics, metabolism)
• Signal Transduction
• Sumoylation
• Transcription Factors (metabolism)
• Transfection
• Up-Regulation