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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, Vijaya Padma, Viswanadha, Huang, Chih‐Yang, Huang, Chih‐Yang
Environmental toxicology 2019 v.34 no.2 pp. 210-218
animal models, apoptosis, cardiotoxicity, caspase-3, collagen, diet, echocardiography, fibrosis, gene overexpression, heart, messenger RNA, rats, staining, transforming growth factor beta, transgenic animals, vimentin
IGF‐IIR activation regulates cardiac remodeling leading to apoptosis. Here, we identified the novel IGF‐IIRα (150 KDa), a truncated IGF‐IIR transcript enhances cardiac apoptosis under high‐salt uptake in transgenic rat model. Echocardiographic analysis revealed decline in ejection fraction and fractional shortening percentage in IGF‐IIRα (TG) rats. We found that IGF‐IIRα TG rats developed severe apoptosis and fibrosis as identified through TUNEL assay and Masson's trichrome staining. Importantly, the heart functioning, apoptosis, and fibrosis were significantly affected under high‐salt conditions in IGF‐IIRα (TG) rats. Significant upregulation of apoptosis was evident from decreased Bcl‐2, p‐AKT, and p‐PI3K expressions with concomitant increase in Bad, cytochrome C, cleaved caspase 3 levels. We found that, IGF‐IIRα highly induced tissue fibrosis through collagen accumulation (col I, col III) and up regulated various fibrotic markers such as tPA, uPA, TGF‐β, and vimentin expressions. The observed upregulation of fibrosis were significantly regulated under high‐salt conditions and their over regulation under IGF‐IIRα over expressions shows the key role of IGF‐IIRα in promoting high‐salt induced fibrosis. During IGF‐IIRα over expression induced cardiotoxicity, under high salt condition, and it destroys the interaction between CHIP and HSF1, which promotes the degradation of HSF1 and results in upregulation of IGF‐IIR/IGF‐IIRα expressions. Altogether, the study unveils novel IGF‐IIRα in the regulation of cardiac apoptosis and fibrosis under high‐salt diet.