NR4A1 contributes to high-fat associated endothelial dysfunction by promoting CaMKII-Parkin-mitophagy pathways

Cell Stress & Chaperones
Pei LiJing Wang

Abstract

Parkin-related mitophagy is vital for endothelial cell viability and the development of atherosclerosis, although the upstream regulatory factor underlying Parkin-mediated mitophagy in endothelial apoptosis and atherosclerosis progression remains unknown. In the present study, we demonstrated that nuclear receptor subfamily 4 group A member 1 (NR4A1) is actually expressed in aortic endothelial cells (AECs) under oxidized low-density lipoprotein (ox-LDL) treatment in vitro or isolated from high-fat treated mice in vivo. Higher NR4A1 levels were associated with AEC apoptosis, mitochondrial dysfunction, and energy disorder. At the molecular level, ox-LDL stimulation increased NR4A1 expression, which evoked Parkin-mediated mitophagy. Excessive mitophagy overtly consumed mitochondrial mass, leading to an energy shortage and mitochondrial dysfunction. However, loss of NR4A1 protected AECs against ox-LDL induced apoptosis by inhibiting excessive mitophagy. Furthermore, we also identified that NR4A1 regulated Parkin activation via post-transcriptional modification by Ca2+/calmodulin-dependent protein kinase II (CaMKII). Activated CaMKII via NR4A1 induced the phosphorylated activation of Parkin. In summary, our data support the role of ...Continue Reading

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Citations

Sep 8, 2018·Journal of Cellular Physiology·Junqin ShengJianxun Feng
Jan 30, 2020·Apoptosis : an International Journal on Programmed Cell Death·Yi ZhuNai-Feng Liu
Dec 3, 2020·Frontiers in Cell and Developmental Biology·Jia Zheng, Chengzhi Lu
Dec 31, 2020·Cells·Ki-Wook KimJesse W Williams
Mar 7, 2021·Cells·Anastasia V PoznyakAlexander N Orekhov
Apr 2, 2021·International Journal of Cardiology·Ampadu O JacksonShiyin Long
Jul 8, 2021·Journal of Cardiovascular Pharmacology·Yibo LiGuoan Zhao
Apr 8, 2020·Aging and Disease·Yibo YangBin Liu

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Methods Mentioned

BETA
Assay
transfection
flow cytometry

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