Dataset Information

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway.

ABSTRACT: Homer1a is the short form of a scaffold protein that plays a protective role in many forms of stress. However, the role of Homer1a in cerebral ischemia/reperfusion (I/R) injury and its potential mechanism is still unknown. In this study, we found that Homer1a was upregulated by oxygen and glucose deprivation (OGD) and that overexpression of Homer1a alleviated OGD-induced lactate dehydrogenase (LDH) release and cell death in cultured cortical neurons. After OGD treatment, the overexpression of Homer1a preserved mitochondrial function, as evidenced by less cytochrome c release, less reactive oxygen species (ROS) production, less ATP and mitochondrial membrane potential (MMP) loss, less caspase-9 activation, and inhibition of endoplasmic reticulum (ER) stress confirmed by the decreased expression of phosphate-PKR-like ER Kinase (p-PERK)/PERK and phosphate- inositol-requiring enzyme 1 (p-IRE1)/IRE1 and immunofluorescence (IF) staining. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator Tunicamycin (TM) with a re-escalated ROS level, increasing ATP and MMP loss. Furthermore, Homer1a overexpression-induced mitochondrial stress attenuation was significantly reversed by activating the PERK pathway with TM and p-IRE1 inhibitor 3,5-dibromosalicylaldehyde (DBSA), as evidenced by increased cytochrome c release, increased ATP loss and a higher ROS level. However, activating the IRE1 pathway with TM and p-PERK inhibitor GSK2656157 showed little change in cytochrome c release and exhibited a moderate upgrade of ATP loss and ROS production in neurons. In summary, these findings demonstrated that Homer1a protects against OGD-induced injury by preserving mitochondrial function through inhibiting the PERK pathway. Our finding may reveal a promising target of protecting neurons from cerebral I/R injury.

SUBMITTER: Wei J

PROVIDER: S-EPMC6428733 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway.

Wei Jialiang J Wu Xiuquan X Luo Peng P Yue Kangyi K Yu Yang Y Pu Jingnan J Zhang Lei L Dai Shuhui S Han Donghui D Fei Zhou Z

Frontiers in cellular neuroscience 20190315

Homer1a is the short form of a scaffold protein that plays a protective role in many forms of stress. However, the role of Homer1a in cerebral ischemia/reperfusion (I/R) injury and its potential mechanism is still unknown. In this study, we found that Homer1a was upregulated by oxygen and glucose deprivation (OGD) and that overexpression of Homer1a alleviated OGD-induced lactate dehydrogenase (LDH) release and cell death in cultured cortical neurons. After OGD treatment, the overexpression of Ho ...[more]

PMID: 30930751

Similar Datasets

Project description:Glucosamine impairs hepatic apolipoprotein B100 (apoB100) production by inducing endoplasmic reticulum (ER) stress and enhancing cotranslational and posttranslational apoB100 degradation (Qiu, W., R. K. Avramoglu, A. C. Rutledge, J. Tsai, and K. Adeli. Mechanisms of glucosamine-induced suppression of the hepatic assembly and secretion of apolipoprotein B-100-containing lipoproteins. J. Lipid Res. 2006. 47: 1749-1761). Here, we report that glucosamine also regulates apoB100 protein synthesis via ER-stress-induced PERK activation. Short-term (4 h) glucosamine treatment of HepG2 cells reduced both cellular (by 62%) and secreted apoB100 (by 43%) without altering apoB100 mRNA. Treatment with proteasomal inhibitors only partially prevented the suppressive effects of glucosamine, suggesting that mechanisms other than proteasomal degradation may also be involved. Glucosamine-induced ER stress was associated with a significantly reduced apoB100 synthesis with no significant change in posttranslational decay rates, suggesting that glucosamine exerted its effect early during apoB biosynthesis. The role of PERK and its substrate, alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha), in the suppressive effects of glucosamine on apoB synthesis was then investigated. Coexpression of apoB15 (normally resistant to intracellular degradation) with wild-type double stranded (ds) RNA activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) in COS-7 cells resulted in a dramatic reduction in the levels of newly synthesized apoB15. Interestingly, cotransfection with apoB15 and a kinase inactive PERK mutant (K618A) increased apoB15 expression. In addition, short-term glucosamine treatment stimulated an increase in phosphorylation of PERK and eIF2alpha. Taken together, these data suggest that in addition to the induction of ER-associated degradation and other degradative pathways, ER stress is associated with suppression of apoB synthesis via a PERK-dependent mechanism.

Project description:ObjectiveThis study investigated the role of Mzb1 in puerarin protection against heart injury and dysfunction in acute myocardial infarction (AMI) mice.MethodsC57BL/6 mice were pretreated with and without puerarin at doses of 50 mg/kg and 100 mg/kg for 14 days before establishing the AMI model. An AMI model was induced by ligating the left descending anterior coronary artery, and AC16 cardiomyocytes were treated with H2O2 in vitro. Echocardiography was performed to measure cardiac function. DHE staining, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, and DCFH-DA oxidative fluorescence staining were used to determine reactive oxygen species (ROS) production in vivo and in vitro. Bioinformatics analysis was used to predict potential upstream transcription factors of Mzb1.ResultsPuerarin dose-dependently reduced myocardial infarction area and injury, accompanied by the improvement of cardiac function in AMI mice. AMI mice manifested an increase in myocardial oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and mitochondrial biogenesis dysfunction, which were inhibited by pretreatment with puerarin. Puerarin also prevented Mzb1 downregulation in the hearts of AMI mice or H2O2-treated AC16 cells. Consistent with the in vivo findings, puerarin inhibited H2O2-induced cardiomyocyte apoptosis, ER stress, and mitochondrial dysfunction, which were attenuated by siRNA Mzb1. Furthermore, the JASPAR website predicted that KLF4 may be a transcription factor for Mzb1. The expression of KLF4 was partially reversed by puerarin in the cardiomyocyte injury model, and KLF4 inhibitor (kenpaullone) inhibited Mzb1 expression and affected its function.ConclusionThese results suggest that puerarin can protect against cardiac injury by attenuating oxidative stress and endoplasmic reticulum stress through upregulating the KLF4/Mzb1 pathway and that puerarin may expand our armamentarium for the prevention and treatment of ischemic heart diseases.

Dataset Information

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway.

Publications

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets