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Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate
lipotoxic brain microvascular injury.
Authors Nyunt T, Britton M, Wanichthanarak K, Budamagunta M, Voss JC, Wilson DW,
Rutledge JC, Aung HH
Submitted By Submitted Externally on 11/24/2019
Status Published
Journal Free radical biology & medicine
Year 2019
Date Published 11/1/2019
Volume : Pages 143 : 25 - 46
PubMed Reference 31356870
Abstract 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.


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