Details

Autor(en) / Beteiligte

• Pandey, Sudhir
• Kuo, Wei‐Wen
• Ho, Tsung‐Jung
• Yeh, Yu‐Lan
• Shen, Chia‐Yao
• Chen, Ray‐Jade
• Chang, Ruey‐Lin
• Pai, Pei‐Ying
• Padma, V. Vijaya
• Huang, Chih‐Yang

Titel

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

Ist Teil von

• Journal of cellular biochemistry, 2019-10, Vol.120 (10), p.16956-16966

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• 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. Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. In this study, we elucidated the functional contribution of a novel stress‐inducible protein insulin‐like growth factor receptor type II α (IGF‐IIRα) in doxorubicin (DOX)‐induced stress and cardiotoxicity. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD‐TG [IGF‐IIRα]), we showed that overexpressing IGF‐IIRα specifically in the heart leads to cardiac structural abnormalities and functional perturbations that were synergistically aggravated by DOX‐induced cardiac stress. This study revealed a new molecular entrant in the pathogenesis of DOX triggered cardiac toxicity, which may add to our existing understanding of molecular mechanisms underlying cardiac damage in DOX‐treated cancer patients.