IL-6/gp130/STAT3 signaling contributed to the activation of the PERK arm of the unfolded protein response in response to chronic β-adrenergic stimulation

Prolonged activation of the PERK branch of the unfolded protein response (UPR) promotes cardiomyocytes apoptosis in response to chronic & beta;-adrenergic stimulation. STAT3 plays a critical role in & beta;-adrenergic functions in the heart. However, whether STAT3 contributed to & beta;-adrenoceptor-mediated PERK activation and how & beta;-adrenergic signaling activates STAT3 remains unclear. This study aimed to investigate whether STAT3-Y705 phosphorylation contributed to the PERK arm acti-vation in cardiomyocytes and if IL-6/gp130 signaling was involved in the chronic & beta;-AR-stimulation-induced STAT3 and PERK arm activation. We found that the PERK phosphorylation was positively associated with STAT3 activation. Wild-type STAT3 plasmids transfection activated the PERK/eIF2 & alpha;/ATF4/CHOP pathway in car-diomyocytes while dominant negative Y705F STAT3 plasmids caused no obvious effect on PERK signaling. Stimulation with isoproterenol produced a significant increase in the level of IL-6 in the cardiomyocyte's supernatants, while IL-6 silence inhibited PERK phosphorylation but failed to attenuate STAT3 activation in response to isoproterenol stimulation. Gp130 silence attenuated isoproterenol-induced STAT3 activation and PERK phosphorylation. Inhibiting IL-6/gp130 pathway by bazedoxifene and inhibiting STAT3 by stattic both reversed isoproterenol-induced STAT3-Y705 phosphorylation, ROS production, PERK activation, IRE1 & alpha; activation, and cardiomyocytes apoptosis in vitro. Bazedoxifene (5 mg/kg/day by oral gavage once a day) exhibited similar effect as carvedilol (10 mg/kg/day by oral gavage once a day) on attenuating chronic isoproterenol (30 mg/kg by abdominal injection once a day, 7 days) induced cardiac systolic dysfunction, cardiac hy-pertrophy and fibrosis in C57BL/6 mice. Meanwhile, bazedoxifene attenuates isoproterenol-induced STAT3-Y705 phosphorylation, PERK/eIF2 & alpha;/ATF4/CHOP acti-vation, IRE1 & alpha; activation, and cardiomyocytes apoptosis to a similar extend as carvedilol in the cardiac tissue of mice. Our results showed that chronic & beta;-adrenoceptor-mediated stimulation activated the STAT3 and PERK arm of the UPR at least partially via IL-6/gp130 pathway. Bazedoxifene has great potential to be used as an alternative to conventional & beta;-blockers to attenuate & beta;-adrenoceptor-mediated maladaptive UPR.

Automated summary

Prolonged activation of PERK branch of UPR promotes cardiomyocytes apoptosis in response to chronic β-adrenergic stimulation. STAT3 plays a critical role in β-adrenergic functions in the heart. This study aimed to investigate whether STAT3 contributed to β-adrenoceptor-mediated PERK activation and how β-adrenergic signaling activates STAT3. Results showed that PERK phosphorylation was positively associated with STAT3 activation. Stimulation with isoproterenol produced an increase in IL-6 level and IL-6/gp130 signaling was involved in STAT3 and PERK activation.