Journal article
Isocitrate dehydrogenase 2 deficiency induces endothelial inflammation via p66sh-mediated mitochondrial oxidative stress
Biochemical and biophysical research communications, Vol.503(3), pp.1805-1811
09/10/2018
DOI: 10.1016/j.bbrc.2018.07.117
PMID: 30072100
Abstract
Isocitrate dehydrogenase 2 (IDH2) is an essential enzyme in the mitochondrial antioxidant system, which produces nicotinamide adenine dinucleotide phosphate, and thereby defends against oxidative stress. We have shown that IDH2 downregulation results in mitochondrial dysfunction and reactive oxygen species (ROS) generation in mouse endothelial cells. The redox enzyme p66shc is a key factor in regulating the level of ROS in endothelial cells. In this study, we hypothesized that IDH2 knockdown-induced mitochondrial dysfunction stimulates endothelial inflammation, which might be regulated by p66shc-mediated oxidative stress. Our results showed that IDH2 downregulation led to mitochondrial dysfunction by decreasing the expression of mitochondrial oxidative phosphorylation complexes I, II, and IV, reducing oxygen consumption, and depolarizing mitochondrial membrane potential in human umbilical vein endothelial cells (HUVECs). The dysfunction not only increased mitochondrial ROS levels but also activated p66shc expression in HUVECs and IDH2 knockout mice. IDH2 deficiency increased intercellular adhesion molecule (ICAM)-1 expression and mRNA levels of pro-inflammatory cytokines (tumor necrosis factor [TNF]-α, and interleukin [IL]-1β) in HUVECs. The mRNA expression of ICAM-1 in endothelial cells and plasma levels of TNF-α and IL-1β were also markedly elevated in IDH2 knockout mice. However, p66shc knockdown rescued IDH2 deficiency-induced mitochondrial ROS levels, monocyte adhesion, ICAM-1, TNF-α, and IL-1β expression in HUVECs. These findings suggest that IDH2 deficiency induced endothelial inflammation via p66shc-mediated mitochondrial oxidative stress.
•IDH2 deficiency triggers severe mitochondrial dysfunction in HUVECs.•IDH2 deficiency induces endothelial inflammation by the increased mitochondrial ROS and p66shc expression.•p66shc mediated IDH2 deficiency-induced inflammatory molecule expression in HUVECs.
Details
- Title: Subtitle
- Isocitrate dehydrogenase 2 deficiency induces endothelial inflammation via p66sh-mediated mitochondrial oxidative stress
- Creators
- Su-jeong Choi - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaShuyu Piao - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaHarsha Nagar - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaSaet-byel Jung - Department of Endocrinology, School of Medicine, Chungnam National University, Daejeon, 301-721, Republic of KoreaSeonhee Kim - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaIkjun Lee - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaSung-min Kim - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaHee-Jung Song - Department of Neurology, Chungnam National University Hospital, Daejeon, 301-721, Republic of KoreaNara Shin - Department of Anatomy & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaDong Woon Kim - Department of Anatomy & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaKaikobad Irani - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USAByeong Hwa Jeon - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of KoreaJeen-Woo Park - School of Life Sciences, College of Natural Science, Kyungpook National University, Taegu, 702-701, Republic of KoreaCuk-Seong Kim - Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon, 301-747, Republic of Korea
- Resource Type
- Journal article
- Publication Details
- Biochemical and biophysical research communications, Vol.503(3), pp.1805-1811
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.bbrc.2018.07.117
- PMID
- 30072100
- ISSN
- 0006-291X
- eISSN
- 1090-2104
- Grant note
- DOI: 10.13039/501100002701, name: Ministry of Education, award: NRF-2014R1A6A1029617; DOI: 10.13039/501100003625, name: Ministry of Health and Welfare, award: HI17C-1202-010018; DOI: 10.13039/501100003725, name: National Research Foundation of Korea
- Language
- English
- Date published
- 09/10/2018
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984047727002771
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