| Institution: | 1. Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan;2. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan;3. Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan;4. Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
Department of Nursing and Management, Jen-Teh Junior College of Medicine, Miaoli, Taiwan;5. Department of Nursing, Mei Ho University, Pingguang Road, Pingtung, Taiwan;6. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;7. Department of Postbaccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan;8. Division of Cardiology, China Medical University Hospital, Taichung, Taiwan;9. Department of Biotechnology, Bharathiar University, Coimbatore, India;10. Department of Translation Research Core, China Medical University Hospital, Taichung, Taiwan |
| Abstract: | Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. Through this study, the functional contribution of insulin-like growth factor receptor type II α (IGF-IIRα) which is a novel stress-inducible protein was explored in doxorubicin-induced cardiac stress. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD-TG IGF-IIRα]) overexpressing IGF-IIRα specifically in heart, we found that IGF-IIRα leads to cardiac structural abnormalities and functional perturbations that were severely aggravated by doxorubicin-induced cardiac stress. Overexpression of IGF-IIRα leads to cumulative elevation of stress associated cardiac hypertrophy and apoptosis factors. There was a significant reduction of survival associated proteins p-Akt and estrogen receptor β/α, and abnormal elevation of cardiac hypertrophy markers such as atrial natriuretic peptide, cardiac troponin-I, and apoptosis-inducing agents such as p53, Bax, and cytochrome C, respectively. IGF-IIRα also altered the expressions of AT1R, ERK1/2, and p38 proteins. Besides, IGF-IIRα also increased the reactive oxygen species production in H9c2 cells which were markedly aggravated by doxorubicin treatment. Together, we showed that IGF-IIRα is a novel stress-induced protein that perturbed cardiac homeostasis and cumulatively exacerbated the doxorubicin-induced cardiac injury that perturbed heart functions and ensuing cardiomyopathy. |
