RETRACTED: Activation of Akt Rescues Endoplasmic Reticulum Stress-Impaired Murine Cardiac Contractile Function via Glycogen Synthase Kinase-3β-Mediated Suppression of Mitochondrial Permeation Pore Opening (Retracted Article)

Aims: The present study was designed to examine the impact of chronic Akt activation on endoplasmic reticulum (ER) stress-induced cardiac mechanical anomalies, if any, and the underlying mechanism involved. Results: Wild-type and transgenic mice with cardiac-specific overexpression of the active mutant of Akt (Myr-Akt) were subjected to the ER stress inducer tunicamycin (1 or 3 mg/kg). ER stress led to compromised echocardiographic (elevated left ventricular end-systolic diameter and reduced fractional shortening) and cardiomyocyte contractile function, intracellular Ca2+ mishandling, and cell survival in wild-type mice associated with mitochondrial damage. In vitro ER stress induction in murine cardiomyocytes upregulated the ER stress proteins Gadd153, GRP78, and phospho-eIF2 alpha, and promoted reactive oxygen species production, carbonyl formation, apoptosis, mitochondrial membrane potential loss, and mitochondrial permeation pore (mPTP) opening associated with overtly impaired cardiomyocyte contractile and intracellular Ca2+ properties. Interestingly, these anomalies were mitigated by chronic Akt activation or the ER chaperon tauroursodeoxycholic acid (TUDCA). Treatment with tunicamycin also dephosphorylated Akt and its downstream signal glycogen synthase kinase 3 beta (GSK3 beta) (leading to activation of GSK3 beta), the effect of which was abrogated by Akt activation and TUDCA. The ER stress-induced cardiomyocyte contractile and mitochondrial anomalies were obliterated by the mPTP inhibitor cyclosporin A, GSK3 beta inhibitor SB216763, and ER stress inhibitor TUDCA. Innovation: This research reported the direct relationship between ER stress and cardiomyocyte contractile and mitochondrial anomalies for the first time. Conclusion: Taken together, these data suggest that ER stress may compromise cardiac contractile and intracellular Ca2+ properties, possibly through the Akt/GSK3 beta-dependent impairment of mitochondrial integrity. Antioxid. Redox Signal. 15, 2407-2424.