Synergistic Cardiac Pathological Hypertrophy Induced By High-Salt Diet In Igf-Iir Alpha Cardiac-Specific Transgenic Rats

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-IIR alpha (150 kDa) play a key role in high-salt induced hypertrophy mechanisms. Cardiac overexpression of IGF-IIR alpha 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-IIR alpha 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 (G alpha q) 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-IIR alpha transgenic rats fed with a high-salt diet. Altogether, from the findings, we demonstrate that IGF-IIR alpha plays a crucial role during high-salt conditions leading to synergistic cardiac hypertrophy.