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

Abstract

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 Ca 2+ 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-eIF2a, 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 Ca 2+ 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 3b (GSK3b) (leading to activation of GSK3b), 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, GSK3b 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 Ca 2+ properties, possibly through the Akt/GSK3b-dependent impairment of mitochondrial integrity. Antioxid. Redox Signal. 15, 2407-2424.

Pressure Overload Regulates Expression of Cytokines, γH2AX, and Growth Arrest- and DNA-Damage Inducible Protein 153 via Glycogen Synthase Kinase-3β in Ischemic-Reperfused Hearts

“…Importantly, inhibition of GSK-3β caused a prominent reduction in GADD153 expression with the effect more marked for the pressure overloaded hearts. This observation is consistent with the emerging role of GSK-3β in regulation of ER stress response and associated GADD153 expression including activation of protein kinase B/Akt ameliorates ER-stress-induced murine cardiac contractile dysfunction via GSK-3β-mediated suppression of MPT pore opening 42 and inhibition of GSK-3β reduces ER stress-induced C/EBP homologous protein (ie, GADD153) expression in neuronal cells. 12 A hallmark feature of IR injury is marked oxidative/nitrosative stress.…”

Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

“…Previous studies also reported that 4-HNE triggered suppression of Akt activity (27), compromised cardiomyocytes mechanical function and protein damage (25). ER stress induction was found to promote carbonyl formation (14,17), whereas carbonyl formation was also upregulated in response to 4-HNE exposure, which was attenuated by ALDH2 overexpression (25). Taken together, the above evidence suggests that the role of ALDH2 against ER stress, at least in part, was attributed to the detoxification of 4-HNE with ALDH2.…”

“…However, the role of Akt signaling in regulation of ER stress is controversial. Activation of Akt was found to rescue the cardiac mechanical function defect induced by ER stress, whereas it did not affect the protein levels of ER stress markers (14,17). Recent studies demonstrated that inhibition of ER stress by intermedin was blocked by the PI3K inhibitor (29).…”

“…Generation and characterization of the ALDH2 KO mice using gene targeting in embryonic stem cells were described in detail previously (15). Given that the ER environment can be perturbed with pharmacological agents through altered redox status, Ca 2+ homeostasis and protein glycosylation in the ER, all mice were injected intraperitoneally with tunicamycin (3 mg/kg) (Sigma-Aldrich, St. Louis, MO, USA) to elicit ER stress for 48 h before assessment of mechanical properties (14).…”

“…On the basis of previous observations in the animal model challenged with tunicamycin (14), the aim of this study was to determine whether ALDH2 knockout (KO) triggers deterioration of cardiac function after ER stress induction in ALDH2 KO mice and whether ALDH2 overexpression may prevent tunicamycin-induced ER stress and apoptosis.…”