Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses

The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIR alpha in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIR alpha overexpression enhanced ER stress markers ATF4, ATF6, IRE1 alpha, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIR alpha concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIR alpha-induced ER stress responses. Altogether, these findings suggested that IGF-IIR alpha contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.

Automated summary

The heart, as a dynamic pumping organ, is constantly working to maintain blood supply, but is vulnerable to various stresses, especially oxidative stress. This study demonstrates the crucial role of IGF-IIR alpha in endoplasmic reticulum stress induction, inhibiting cellular stress coping proteins and increasing pro-apoptotic factors, ultimately leading to cardiomyocyte damage.