Publication: Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury
1
Issued Date
2019-11-01
Resource Type
ISSN
18734596
08915849
08915849
Other identifier(s)
2-s2.0-85069883701
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Free Radical Biology and Medicine. Vol.143, (2019), 25-46
Suggested Citation
Tun Nyunt, Monica Britton, Kwanjeera Wanichthanarak, M. Budamagunta, John C. Voss, Dennis W. Wilson, John C. Rutledge, Hnin H. Aung Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury. Free Radical Biology and Medicine. Vol.143, (2019), 25-46. doi:10.1016/j.freeradbiomed.2019.07.024 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/50044
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury
Other Contributor(s)
Abstract
© 2019 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.