Apoptosis of cardiomyocytes in diabetic cardiomyopathy involves overexpression of glycogen synthase kinase-3β

Abstract To evaluate the role of glycogen synthase kinase-3β (GSK-3β) in the apoptosis of cardiomyocytes in diabetic cardiomyopathy (DCM). Diabetes mellitus (DM) in rats was induced by intraperitoneal injection of 1% streptozotocin (STZ), and lithium chloride (LiCl) was used to decrease the expression of GSK-3β. Hematoxylin/eosin (HE) staining and the terminal deoxyribonucleotide transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay was conducted to evaluate the pathological injury and apoptosis of cardiomyocytes respectively. Western blot was applied to detect the protein expressions of Cleaved-caspase 3, caspase 3, Bax and Bcl-2 in rat cardiomyocytes. Real-time polymerase chain reaction (RT-PCR) was applied to detect the gene expressions of phosphoinositide 3-kinases (PI3K), Akt, and GSK-3β in rat cardiomyocytes. DM-induced cardiomyocyte injuries, which were presented as capillary basement membrane thickening, interstitial fibrosis, cardiomyocyte hypertrophy and necrosis in HE staining and increased apoptosis detected by TUNEL assay. When comparing with the control group, the mRNA expression of PI3K and Akt in DM group obviously decreased but the mRNA expression of GSK-3β obviously elevated (P < 0.05). In addition, the ratio of Cleaved-caspase 3/caspase 3 and Bax/Bcl-2 were notably increased in DM group compared with control group (P < 0.05). LiCl, as an inhibitor of GSK-3 apparently reduced the expression of GSK-3β mRNA (P < 0.05) but not the PI3K and Akt comparing with the DM group. LiCl also attenuated the myocardial injury and apoptosis induced by DM. The myocardial injury induced by DM is associated with the up-regulation of GSK-3β. LiCl inhibited the expression of GSK-3β and myocardial apoptosis in diabetic myocardium.

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Cramming the causative mechanism of glycogen synthase kinase-3β mediated by ischemic preconditioning against ovariectomy challenged rat heart

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i1.4158 ◽

2021 ◽

Vol 12 (1) ◽

pp. 669-675

Author(s):

Vishal Kumar Vishwakarma ◽

Tarique Mahmood Ansari ◽

Prabhat Kumar Upadhyay ◽

Ritesh Kumar Srivastav ◽

Farogh Ahsan ◽

...

Keyword(s):

Ischemic Preconditioning ◽

Rat Heart ◽

Glycogen Synthase ◽

Protective Action ◽

Isolated Rat Heart ◽

Glycogen Synthase Kinase ◽

Control Group ◽

Glycogen Synthase Kinase 3Β ◽

Mptp Opening ◽

Gsk 3Β

High risks of cardiovascular diseases in women are associated with low estrogen levels. Ischemic preconditioning (IPC) exhibits protection in the heart by Glycogen synthase kinase-3β (GSK-3β) phosphorylation that inhibits the mPTP opening, and this protective action of IPC is attenuated by estrogen deficiency. An experiment was performed on female Wistar rats with/without ovariectomy (OVX). Isolated rat heart was attached with perfusion assembly. Infract size, coronary flow, LDH, CKMB and histopathology were estimated. Sham control group decreased the LDH, CKMB and infract size in normal rat heart. The IPC mediated protection of heart was attenuated in OVX rat heart. Inhibition of GSK-3β is found to enhance the threshold of mPTP opening during reperfusion. The treatment with atractyloside stuck significantly the protection of heart of IPC in normal and OVX rat heart. These observations show that downregulation of GSK-3β through an impaired opening of mPTP during reperfusion and GSK-3β might be potential adjuvant to IPC against cardiac injury in OVX challenged rats.

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Retracted: Phosphorylated Glycogen Synthase Kinase-3β (GSK-3β) Improves Cognition in Rats with Diabetes-Associated Cognitive Decline

Medical Science Monitor ◽

10.12659/msm.919343 ◽

2019 ◽

Vol 25 ◽

pp. 6291-6291

Author(s):

Boxi Ke ◽

Rong Lu ◽

Xu Zhang

Keyword(s):

Cognitive Decline ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Gsk 3Β

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Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3β and NF-κB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02045-17 ◽

2018 ◽

Vol 62 (6) ◽

pp. e02045-17 ◽

Cited By ~ 4

Author(s):

Chia-Ling Chen ◽

Miao-Huei Cheng ◽

Chih-Feng Kuo ◽

Yi-Lin Cheng ◽

Ming-Han Li ◽

...

Keyword(s):

Nitric Oxide ◽

Nadph Oxidase ◽

Nuclear Translocation ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Streptococcal Toxic Shock Syndrome ◽

Glycogen Synthase Kinase 3Β ◽

Diphenylene Iodonium ◽

Group A ◽

Gsk 3Β

ABSTRACTGroup AStreptococcus(GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phoxand subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3β (GSK-3β) activation, and subsequent NF-κB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3β/NF-κB/NO signaling pathway.

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Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia

Mediators of Inflammation ◽

10.1155/2020/7860829 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jingjin Li ◽

Chonglong Shi ◽

Zhengnian Ding ◽

Wenjie Jin

Keyword(s):

Cognitive Dysfunction ◽

Lithium Chloride ◽

Glycogen Synthase ◽

Postoperative Cognitive Dysfunction ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Central Nervous System Complication ◽

Proinflammatory Mediators ◽

M1 Polarization ◽

Gsk 3Β

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3β (GSK-3β) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3β in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3β, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3β is a key contributor to POCD and a potential target of neuroprotective strategies.

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