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 NR4A1/CaMKII/Parkin/mitophagy in AEC apoptosis and atherosclerosis formation and provide new insights into treating atherosclerosis with respect to endothelial viability, mitophagy, and NR4A1.
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This study was supported by grants from National Natural Science Foundation of China (Number 81501195). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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PL, YZB, and JW were involved in conception and design, performance of experiments, data analysis and interpretation, and manuscript writing; XZ, LYT, and TT were involved in data analysis and interpretation; JR, YA, and JW were involved in conception and design, data analysis and interpretation, financial support, and final approval of manuscript.
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Li, P., Bai, Y., Zhao, X. et al. NR4A1 contributes to high-fat associated endothelial dysfunction by promoting CaMKII-Parkin-mitophagy pathways. Cell Stress and Chaperones 23, 749–761 (2018). https://doi.org/10.1007/s12192-018-0886-1
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DOI: https://doi.org/10.1007/s12192-018-0886-1