Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury
Autor: | John C. Voss, Hnin Hnin Aung, Madhu S. Budamagunta, Tun Nyunt, Monica Britton, Dennis W Wilson, Kwanjeera Wanichthanarak, John C. Rutledge |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Small interfering RNA Apoptosis Medical Biochemistry and Metabolomics Mitochondrion Cardiovascular medicine.disease_cause Biochemistry Brain microvascular endothelial cells 0302 clinical medicine Superoxides 2.1 Biological and endogenous factors Glycolysis RNA-Seq Aetiology RNA Small Interfering chemistry.chemical_classification Brain Postprandial Period Mitochondria Cell biology Neurological Tumor necrosis factor alpha Protons Signal transduction Signal Transduction Biochemistry & Molecular Biology Activating transcription factor 3 Lipolysis Triglyceride-rich lipoproteins Oxidative phosphorylation Small Interfering Article Medicinal and Biomolecular Chemistry 03 medical and health sciences Oxygen Consumption Physiology (medical) Genetics medicine Humans Inflammation Reactive oxygen species Activating Transcription Factor 3 Endothelial Cells Genetic Variation Mitochondrial oxidative stress Atherosclerosis Oxidative Stress 030104 developmental biology chemistry Brain Injuries Microvessels RNA Biochemistry and Cell Biology Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress DNA Damage |
Zdroj: | Free Radic Biol Med |
ISSN: | 0891-5849 |
Popis: | Elevation of blood triglycerides, primarily triglyceride-rich lipoproteins (TGRL), is an independent risk factor for cardiovascular disease and vascular dementia (VaD). Accumulating evidence indicates that both atherosclerosis and VaD are linked to vascular inflammation. However, the role of TGRL in vascular inflammation, which increases risk for VaD, remains largely unknown and its underlying mechanisms are still unclear. We strived to determine the effects of postprandial TGRL exposure on brain microvascular endothelial cells, the potential risk factor of vascular inflammation, resulting in VaD. We showed in Aung et al., J Lipid Res., 2016 that postprandial TGRL lipolysis products (TL) activate mitochondrial reactive oxygen species (ROS) and increase the expression of the stress-responsive protein, activating transcription factor 3 (ATF3), which injures human brain microvascular endothelial cells (HBMECs) in vitro. In this study, we deployed high-throughput sequencing (HTS)-based RNA sequencing methods and mito stress and glycolytic rate assays with an Agilent Seahorse XF analyzer and profiled the differential expression of transcripts, constructed signaling pathways, and measured mitochondrial respiration, ATP production, proton leak, and glycolysis of HBMECs treated with TL. Conclusions: TL potentiate ROS by mitochondria which activate mitochondrial oxidative stress, decrease ATP production, increase mitochondrial proton leak and glycolysis rate, and mitochondria DNA damage. Additionally, CPT1A1 siRNA knockdown suppresses oxidative stress and prevents mitochondrial dysfunction and vascular inflammation in TL treated HBMECs. TL activates ATF3-MAPKinase, TNF, and NRF2 signaling pathways. Furthermore, the NRF2 signaling pathway which is upstream of the ATF3-MAPKinase signaling pathway, is also regulated by the mitochondrial oxidative stress. We are the first to report differential inflammatory characteristics of transcript variants 4 (ATF3-T4) and 5 (ATF3-T5) of the stress responsive gene ATF3 in HBMECs induced by postprandial TL. Specifically, our data indicates that ATF3-T4 predominantly regulates the TL-induced brain microvascular inflammation and TNF signaling. Both siRNAs of ATF3-T4 and ATF3-T5 suppress cells apoptosis and lipotoxic brain microvascular endothelial cells. These novel signaling pathways triggered by oxidative stress-responsive transcript variants, ATF3-T4 and ATF3-T5, in the brain microvascular inflammation induced by TGRL lipolysis products may contribute to pathophysiological processes of vascular dementia. |
Databáze: | OpenAIRE |
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