TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension
TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension
复制标题
DOI：
10.1152/ajpheart.00314.2020
复制
发表时间：
2020-11-01
影响因子：
4.8
通讯作者：
Matoba, Satoaki
中科院分区：
文献类型：
--
作者：
Yamanaka, Ryoetsu;Hoshino, Atsushi;Matoba, Satoaki
肺动脉高压（PAH）是一种难治性疾病。其预后仍然较差；因此，建立新的治疗靶点刻不容缓。 TP53 诱导的糖酵解和凋亡调节因子 (TIGAR) 是 p53 的下游靶标，具有抑制自噬和活性氧 (ROS) 的功能。最近，p53 被证明可以抑制 PAH 进展。由于已知抑制自噬和 ROS 可以改善 PAH，因此我们研究了 TIGAR 对 PAH 进展的影响。我们使用缺氧诱导的 PH 模型比较了 TIGAR 缺陷敲除 (KO) 小鼠和野生型 (WT) 小鼠之间的肺动脉高压 (PH) 发展情况。使用人肺动脉平滑肌细胞 (PASMC) 进行小干扰 RNA (siRNA) 体外实验，以研究可能的分子机制。通过对右心室压力、右心室重量和死亡率的分析，我们得出结论，TIGAR KO 小鼠缺氧诱导的 PH 发展明显高于 WT 小鼠。病理学检查显示TIGAR KO小鼠肺小动脉内侧增厚和细胞增殖增加。 TIGAR KO 小鼠的自噬和 ROS 活性也有所增加。 siRNA 敲低 TIGAR 会增加细胞增殖和迁移，加剧自噬，并增加缺氧期间 ROS 的产生。氯喹的自噬抑制和 N-乙酰半胱氨酸的 ROS 抑制减弱了 TIGAR 敲低和缺氧暴露引起的 PASMC 的增殖和迁移。 TIGAR 通过抑制自噬和 ROS 抑制 PASMC 的增殖和迁移，从而改善缺氧诱导的 PH。因此，TIGAR 可能是 PAH 的一个有前途的治疗靶点。新消息和值得注意的肺动脉高压是一种难治性疾病。 TP53 诱导的糖酵解和凋亡调节因子 (TIGAR) 是 p53 的下游靶标，具有抑制自噬和活性氧 (ROS) 的功能。通过使用 TIGAR 缺陷型敲除小鼠和人肺动脉平滑肌细胞，我们发现 TIGAR 通过抑制自噬和 ROS 来抑制 PASMC 的增殖和迁移，从而改善缺氧诱导的 PH。 TIGAR 将成为 PAH 有前景的治疗靶点。
Pulmonary arterial hypertension (PAH) is a refractory disease. Its prognosis remains poor; hence, establishment of novel therapeutic targets is urgent. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). Recently, p53 was shown to suppress PAH progression. Because inhibition of autophagy and ROS is known to improve PAH, we examined the effect of TIGAR on PAH progression. We compared pulmonary hypertension (PH) development between TIGAR-deficient knockout (KO) and wild-type (WT) mice using a hypoxia-induced PH model. Human pulmonary artery smooth muscle cells (PASMCs) were used for in vitro experiments with small interfering RNA (siRNA) to investigate the possible molecular mechanisms. From the analysis of right ventricular pressure, right ventricular weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation were increased in TIGAR KO mice. Autophagy and ROS activity were also increased in TIGAR KO mice. TIGAR knockdown by siRNA increased cell proliferation and migration, exacerbated autophagy, and increased ROS generation during hypoxia. Autophagy inhibition by chloroquine and ROS inhibition by N-ace-tylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. Thus, TIGAR might be a promising therapeutic target for PAH.NEW & NOTEWORTHY Pulmonary arterial hypertension is a refractory disease. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). By using TIGAR-deficient knockout mice and human pulmonary artery smooth muscle cells, we found that TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. TIGAR will be a promising therapeutic target for PAH.