Nuclear receptor Nur77 protects against oxidative stress by maintaining mitochondrial homeostasis via regulating mitochondrial fission and mitophagy in smooth muscle cell
Graphical abstract
Introduction
The renin-angiotensin-aldosterone system (RAAS) is the major hormonal system that involved in the regulation of cardiovascular function [1,2]. AngII, a potent vasoconstrictive peptide hormone of RAAS, has gained notable attention as a therapeutic target of various cardiovascular diseases such as abdominal aortic aneurysm (AAA) [3,4], hypertension [5], and heart failure [6]. Abnormal activation of RAAS results in an augmented burden of vascular walls, which is partially linked to sustained responses of VSMCs to high levels of AngII, leading to VSMC dysfunction and vascular diseases [7].
Oxidative stress is a primary factor leading to vascular damage under AngII stimulation [8]. Generation of reactive oxygen species (ROS) by damaged mitochondria contributes to numerous physiologic [9] and pathologic processes including metabolic process [10] and cell death [11,12]. Maintenance of mitochondrial homeostasis depends on the restricted quality control accomplished by several molecular machineries that related to mitochondrial biogenesis, mitochondrial dynamics (fission and fusion), and mitophagy [[13], [14], [15]]. Recent studies show that disrupted mitochondrial dynamics are implicated in AAA [16] and hypertension [17], which are particularly associated with VSMCs dysfunction. However, the underlying mechanisms referred to mitochondrial damage in VSMCs under AngII challenge remain elusive.
Nur77/NR4A1 is an orphan nuclear receptor that belongs to NR4A family. These receptors sense changes of microenvironment and control physiological and pathological processes including cellular proliferation, angiogenesis, and cell death through genomic and non-genomic actions [18]. Apart from transcriptional regulation, Nur77 could translocate to mitochondria and inhibit inflammation and oxidative stress through activating autophagy [19]. However, the role of Nur77 in mitochondrial homeostasis and oxidative stress in the setting of AngII challenge is still poorly understood. In this study, we unveil that Nur77 regulates oxidative stress by sustaining mitochondrial homeostasis via attenuating mitochondria fission process and promoting mitophagy under AngII challenge both in vitro and in vivo, supporting the therapeutic potential of Nur77 targeting in vascular diseases.
Section snippets
Animal experiment protocols
Animal experiments were approved by the Animal Ethics Committee of Renji Hospital (RJ2018-1012) and followed the National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals. Nur77 global knockout mice were generated using CRISPR/Cas9 technology as described previously [20]. The efficiency of Nur77 knockout was shown in Fig. S1. ApoE−/− mice were obtained from the Shanghai Model Organisms Center. ApoE−/-Nur77−/− mice were generated by crossing Nur77−/− mice with AopE
Nur77 deficiency aggravates AngII-induced oxidative stress in VSMCs
We first investigated whether Nur77 regulated AngII-induced oxidative stress in VSMCs isolated from aortas. As shown in Fig. 1A, AngII remarkably induced the ROS production in VSMCs as revealed by DHE staining. Of note, Nur77 knockout further increased ROS generation in AngII-treated VSMCs (Fig. 1A), indicating a protective role of Nur77 against oxidative stress. Similarly, knockdown of Nur77 by transfected with specific siRNA in human VSMCs (hASMCs) also increased ROS generation compared with
Discussion
In the current study, we provided new insights into the protective role of Nur77 in regulation of mitochondrial homeostasis and oxidative stress in the setting of AngII stimulation. First, Nur77 deficiency exacerbated oxidative stress in AngII-treated VSMCs, which was accompanied by disrupted mitochondrial dynamics. Second, Nur77 specifically inhibited mitochondrial fission but not fusion process by transcriptionally repressed the expressions of mitochondrial fission related genes Fis1 and Drp1
Author contributions
Qin Shao designed the study; Na Geng, Taiwei Chen and Long Chen conducted the experiments, analyzed the data, and wrote the paper; Hengyuan Zhang, Qingqing Xiao and Zhenyu Tao performed experiments; Lingyue Sun, Yuyan Lyu and Xinyu Che participated in the animal models; Qin Shao reviewed and edited the manuscript.
Disclosures
None.
Funding
This study was supported by Grants from the National Natural Science Foundation of China (81870338, 81570390).
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Na Geng, Taiwei Chen, Long Chen contributed equally to this work.