Overexpression of IGF‐IIRα regulates cardiac remodeling and aggravates high salt induced apoptosis and fibrosis in transgenic rats

Chang, Ruey Lin; Nithiyanantham, Srinivasan; Kuo, Wei Wen; Pai, Pei Ying; Chang, Tung Ti; Lai, Chao Hung; Chen, Ray Jade; Padma, Viswanadha Vijaya; Huang, Chih‐Yang

doi:10.1002/tox.22676

Cited by 12 publications

(36 citation statements)

References 37 publications

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“…But in some important parameters we observed a significant difference between WT and TG in IVSd, LVIDd, LVIDs, SV and LVs mass. Chang et al [11] reported that ejection fraction and fractional shortening was down regulated in TG, WT-HD and TG-HD compared to the WT rats. In addition, IGF-IIRα regulates cardiac apoptosis through cytochrome C/caspase 3 activation with decreased expression of survival proteins and cardiac fibrosis through uPA/tPA/TGF-β signaling and aggravates in high-salt condition.…”

Section: Discussionmentioning

confidence: 99%

“…IGF-IIRα regulates cardiac apoptosis through down-regulation of survival proteins AKT/PI3K signaling and up-regulation of caspase 3 activation. In addition, overexpression of IGF-IIRα regulates cardiac fibrosis through uPA/tPA/TGF-β signaling and higher collagen accumulation and further aggravated its effect in high-salt condition [11]. In this study, we aimed to identify whether novel IGF-IIRα is involved in cardiac hypertrophy and further its functional role in high-salt induced hypertensive heart failure in vivo .…”

Section: Introductionmentioning

confidence: 99%

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Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats

et al. 2019

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Stress-induced cardiac hypertrophy leads to heart failure. Our previous studies demonstrate that insulin-like growth factor—II receptor (IGF-IIR) signaling is pivotal to hypertrophy regulation. In this study, we show a novel IGF-IIR alternative spliced transcript, IGF-IIRα (150 kDa) play a key role in high-salt induced hypertrophy mechanisms. Cardiac overexpression of IGF-IIRα and high-salt diet influenced cardiac dysfunction by increasing pathophysiological changes with up-regulation of hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We found that, cardiac hypertrophy under high-salt conditions were amplified in the presence of IGF-IIRα overexpression. Importantly, high-salt induced angiotensin II type I receptor (AT1R) up regulation mediated IGF-IIR expressions via upstream mitogen activated protein kinase (MAPK)/silent mating type information regulation 2 homolog 1 (SIRT1)/heat shock factor 1 (HSF1) pathway. Further, G-coupled receptors (Gαq) activated calcineurin/nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3)/protein kinase C (PKC) signaling was significantly up regulated under high-salt conditions. All these effects were observed to be dramatically over-regulated in IGF-IIRα transgenic rats fed with a high-salt diet. Altogether, from the findings, we demonstrate that IGF-IIRα plays a crucial role during high-salt conditions leading to synergistic cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats

et al. 2019

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“…A multitude of studies have implicated DOX in the perturbation of the autophagic process during the development of cardiomyopathies, whereby autophagy acts as a double-edged sword, either maintaining cellular protein homeostasis during stresses or culminating in cell death (14,18). In this study, we showed that DOX-induced autophagic derangement involves partial contribution from IGF-IIR␣, which was recently identified as a novel stress-inducible protein causing cardiac hypertrophy and apoptosis (1). The results indicate that IGF-IIR␣ overexpression compromises downstream autophagic machinery leading to nonclearance of damaged proteins/organelles in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 66%

“…All wild-type (WT) Sprague-Dawley (SD) rats and transgenic rats [SD-TG (IGF-IIR␣)] were housed at a constant temperature (22°C) on a 12-h light-dark cycle with food and tap water. The transgenic animals were generated as described previously (1). Pro-nuclear microinjection was performed to insert full-length IGF-IIR␣-pcDNA3.1-myc-His construct driven by ␣-myosin heavy chain (␣-MHC) cardiac-specific promoter and develop IGF-IIR␣ overexpression transgenic rats (TG).…”

Section: Methodsmentioning

confidence: 99%

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

Kuo

Shen

et al. 2019

American Journal of Physiology-Cell Physiology

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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.

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“…IGF-IIRα is a 150 kDa, newly identified stress-inducible protein whose increased expression in the heart leads to the development of pathological changes in the heart. 8 Not much is known about the physiological or pathological functions of IGF-IIRα; therefore, in this study, we investigated the detailed biological role and molecular mechanisms of IGF-IIRα in the development of cardiac function impairment and cardiomyopathies in DOX-induced cardiac stresses.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

Pandey

Kuo

et al. 2019

J of Cellular Biochemistry

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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.

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Overexpression of IGF‐IIRα regulates cardiac remodeling and aggravates high salt induced apoptosis and fibrosis in transgenic rats

Cited by 12 publications

References 37 publications

Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats

Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats

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

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

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