Your browser doesn't support javascript.
loading
Insulin-like growth factor II receptor-α is a novel stress-inducible contributor to cardiac damage underpinning doxorubicin-induced oxidative stress and perturbed mitochondrial autophagy.
Pandey, Sudhir; Kuo, Wei-Wen; Shen, Chia-Yao; Yeh, Yu-Lan; Ho, Tsung-Jung; Chen, Ray-Jade; Chang, Ruey-Lin; Pai, Pei-Ying; Viswanadha, Vijaya Padma; Huang, Chih-Yang; Huang, Chih-Yang.
Afiliação
  • Pandey S; Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.
  • Kuo WW; Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
  • Shen CY; Department of Nursing, Mei Ho University, Pingtung, Taiwan.
  • Yeh YL; Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.
  • Ho TJ; Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
  • Chen RJ; Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan.
  • Chang RL; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • Pai PY; School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
  • Viswanadha VP; Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.
  • Huang CY; Department of Biotechnology, Bharathiar University, Coimbatore, India.
  • Huang CY; Translation Research Core, China Medical University Hospital, Taichung, Taiwan.
Am J Physiol Cell Physiol ; 317(2): C235-C243, 2019 08 01.
Article em En | MEDLINE | ID: mdl-31116582
ABSTRACT
Doxorubicin (DOX) is an anthracycline antibiotic commonly employed for the treatment of various cancers. However, its therapeutic uses are hampered by side effects associated with cumulative doses during the course of treatment. Whereas deregulation of autophagy in the myocardium has been involved in a variety of cardiovascular diseases, the role of autophagy in DOX-induced cardiomyopathy remains debated. Our earlier studies have shown that DOX treatment in a rat animal model leads to increased expression of the novel stress-inducible protein insulin-like growth factor II receptor-α (IGF-IIRα) in cardiac tissues, which exacerbated the cardiac injury by enhancing oxidative stress and p53-mediated mitochondria-dependent cardiac apoptosis. Through this study, we investigated the contribution of IGF-IIRα to dysregulation of autophagy in heart using both in vitro H9c2 cells (DOX treated, 1 µM) and in vivo transgenic rat models (DOX treated, 5 mg/kg ip for 6 wk) overexpressing IGF-IIRα specifically in the heart. We found that IGF-IIRα primarily localized to mitochondria, causing increased mitochondrial oxidative stress that was severely aggravated by DOX treatment. This was accompanied by a significant perturbation in mitochondrial membrane potential and increased leakage of cytochrome c, causing increased cleaved caspase-3 activity. There were significant alterations in phosphorylated AMP-activated protein kinase (p-AMPK), phosphorylated Unc-51 like kinase-1 (p-ULK1), PARKIN, PTEN-induced kinase 1 (PINK1), microtubule-associated protein 1 light chain 3 (LC3), and p62 proteins, which were more severely disrupted under the combined effect of IGF-IIRα overexpression plus DOX. Finally, LysoTracker Red staining showed that IGF-IIRα overexpression causes lysosomal impairment, which was rescued by rapamycin treatment. Taken together, we found that IGF-IIRα leads to mitochondrial oxidative stress, decreased antioxidant levels, disrupted mitochondrial membrane potential, and perturbed mitochondrial autophagy contributing to DOX-induced cardiomyopathy.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doxorrubicina / Receptor IGF Tipo 2 / Estresse Oxidativo / Miócitos Cardíacos / Mitofagia / Cardiopatias / Mitocôndrias Cardíacas / Antibióticos Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Am J Physiol Cell Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Taiwan

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doxorrubicina / Receptor IGF Tipo 2 / Estresse Oxidativo / Miócitos Cardíacos / Mitofagia / Cardiopatias / Mitocôndrias Cardíacas / Antibióticos Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Am J Physiol Cell Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Taiwan