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.

β-catenin/LEF1/IGF-IIR Signaling Axis Galvanizes the Angiotensin-II- induced Cardiac Hypertrophy

“…Through this study, we examined the impact of β-catenin in Ang-II induced hypertrophy responses and demonstrated that IGF-IIR expression could be regulated by β-catenin/LEF1 leading to pathological cardiac hypertrophy signaling. Our earlier studies have shown that abnormal activation of IGF-IIR signaling pathway during cardiac stresses such as elevated Ang II levels [3], or high glucose [5], or drug-induced (doxorubicin) cardiotoxicity [12,13] could lead to increased hypertrophy, fibrosis, and cardiac apoptosis paving the way for heart failure. Besides, we showed that enhancement of β-catenin in cardiomyocytes promotes apoptosis and fibrosis during cardiac stresses such as myocardial infarction (MI) or diabetes [14].…”

Insulin‐like growth factor II receptor alpha overexpression in heart aggravates hyperglycemia‐induced cardiac inflammation and myocardial necrosis

“…Both in vitro and in vivo models have shown that MAPK signaling hypertrophy and mitochondrial-dependent apoptosis are activated; however, the PI3K-AKT survival cascade is attenuated when IGF-IIRα is specifically expressed in cardiomyocytes and cardiac tissues. 43 IGF-IIRα overexpression in the heart not only causes pathological heart, but also leads to hypertrophic kidney, 44 liver, and testis (unpublished data) in the transgenic rats. In the diabetic transgenic rats, collagen accumulation, renal tubular damage, and renal fibrosis are present in the pathological kidney by enhancement of STAT3 associated mechanism.…”

“…Similarly, doxorubicin‐induced functional and structural anomalies in the heart can be enhanced by IGF‐IIRα expression. Both in vitro and in vivo models have shown that MAPK signaling hypertrophy and mitochondrial‐dependent apoptosis are activated; however, the PI3K‐AKT survival cascade is attenuated when IGF‐IIRα is specifically expressed in cardiomyocytes and cardiac tissues 43 . IGF‐IIRα overexpression in the heart not only causes pathological heart, but also leads to hypertrophic kidney, 44 liver, and testis (unpublished data) in the transgenic rats.…”

IGF IIRα-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats

“…Our previous studies show that IGFIIR is expressed during late stage cardiac events and an alternative splicing variant of IGFIIR named IGF-IIRα has been identified in pathological heart [ 11 , 12 ]. Elevated expression of IGF-IIRα during pathological conditions like diabetes and high salt worsens the cardiac performance and increases tissue damages [ 13 – 15 ]. A transgenic IGFIIRα overexpression rat model was created with cardiac specific Myh6 promoter.…”