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
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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