SUMO1 对 Vps34 的 SUMOylation 通过激活自噬促进肺动脉高压中血管平滑肌细胞的表型转换。
SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension.
机构信息
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, OH, 44195, USA.
出版信息
Pulm Pharmacol Ther. 2019 Apr;55:38-49. doi: 10.1016/j.pupt.2019.01.007. Epub 2019 Jan 28.
INTRODUCTION
Pulmonary arterial hypertension (PAH) is a life-threatening disease without effective therapies. PAH is associated with a progressive increase in pulmonary vascular resistance and irreversible pulmonary vascular remodeling. SUMO1 (small ubiquitin-related modifier 1) can bind to target proteins and lead to protein SUMOylation, an important post-translational modification with a key role in many diseases. However, the contribution of SUMO1 to PAH remains to be fully characterized.
METHODS
In this study, we explored the role of SUMO1 in the dedifferentiation of vascular smooth muscle cells (VSMCs) involved in hypoxia-induced pulmonary vascular remodeling and PAH in vivo and in vitro.
RESULTS
In a mouse model of hypoxic PAH, SUMO1 expression was significantly increased, which was associated with activation of autophagy (increased LC3b and decreased p62), dedifferentiation of pulmonary arterial VSMCs (reduced α-SMA, SM22 and SM-MHC), and pulmonary vascular remodeling. Similar results were obtained in a MCT-induced PAH model. Overexpression of SUMO1 significantly increased VSMCs proliferation, migration, hypoxia-induced VSMCs dedifferentiation, and autophagy, but these effects were abolished by inhibition of autophagy by 3-MA in aortic VSMCs. Furthermore, SUMO1 knockdown reversed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, SUMO1 promotes Vps34 SUMOylation and the assembly of the Beclin-1-Vps34-Atg14 complex, thereby inducing autophagy, whereas Vps34 mutation K840R reduces Vps34 SUMOylation and inhibits VSMCs dedifferentiation.
DISCUSSION
Our data uncovers an important role of SUMO1 in VSMCs proliferation, migration, autophagy, and phenotypic switching (dedifferentiation) involved in pulmonary vascular remodeling and PAH. Targeting of the SUMO1-Vps34-autophagy signaling axis may be exploited to develop therapeutic strategies to treat PAH.
简介
肺动脉高压（PAH）是一种危及生命的疾病，目前尚无有效的治疗方法。PAH 与肺血管阻力的进行性增加和不可逆的肺血管重构有关。SUMO1（小泛素相关修饰物 1）可以与靶蛋白结合，导致蛋白质 SUMO 化，这是一种重要的翻译后修饰，在许多疾病中起着关键作用。然而，SUMO1 对 PAH 的贡献仍有待充分描述。
方法
在这项研究中，我们探讨了 SUMO1 在缺氧诱导的肺血管重构和体内、体外 PAH 中血管平滑肌细胞（VSMCs）去分化中的作用。
结果
在缺氧性 PAH 小鼠模型中，SUMO1 表达显著增加，这与自噬的激活（LC3b 增加和 p62 减少）、肺动脉 VSMCs 的去分化（α-SMA、SM22 和 SM-MHC 减少）和肺血管重构有关。在 MCT 诱导的 PAH 模型中也得到了类似的结果。SUMO1 的过表达显著增加了 VSMCs 的增殖、迁移、缺氧诱导的 VSMCs 去分化和自噬，但这些作用在主动脉 VSMCs 中通过 3-MA 抑制自噬而被消除。此外，SUMO1 的敲低逆转了缺氧诱导的 PASMC 增殖和迁移。在机制上，SUMO1 促进了 Vps34 的 SUMO 化和 Beclin-1-Vps34-Atg14 复合物的组装，从而诱导自噬，而 Vps34 突变 K840R 减少了 Vps34 的 SUMO 化并抑制了 VSMCs 的去分化。
讨论
我们的数据揭示了 SUMO1 在 VSMCs 增殖、迁移、自噬和表型转换（去分化）中的重要作用，这些作用涉及肺血管重构和 PAH。针对 SUMO1-Vps34-自噬信号轴可能被开发为治疗 PAH 的治疗策略。
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