Upregulation of IGF-IIRα intensifies doxorubicin-induced cardiac damage.

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.

• Authors: Sudhir Pandey, Wei-Wen Kuo, Tsung-Jung Ho, Yu-Lan Yeh, Chia-Yao Shen, Ray-Jade Chen, Ruey-Lin Chang, Pei-Ying Pai, V Vijaya Padma, Chih-Yang Huang, Chih-Yang Huang
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 120 Issue 10 Pg. 16956-16966 (10 2019) ISSN: 1097-4644 [Electronic] United States
• PMID: 31104312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Antibiotics, Antineoplastic
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Reactive Oxygen Species
• Receptor, IGF Type 2
• Doxorubicin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Apoptosis (drug effects)
• Cardiomegaly (chemically induced)
• Cardiomyopathies (chemically induced)
• Cardiotoxicity (pathology)
• Cell Line
• Doxorubicin (toxicity)
• Estrogen Receptor alpha (metabolism)
• Estrogen Receptor beta (metabolism)
• Heart (anatomy & histology)
• Heart Defects, Congenital (chemically induced)
• Myocytes, Cardiac (metabolism)
• Oxidative Stress (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Transgenic
• Reactive Oxygen Species (metabolism)
• Receptor, IGF Type 2 (biosynthesis, genetics)
• Signal Transduction (drug effects)