Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
Faculty of Health Care, Tenri Health Care University, Tenri, Nara, Japan.
Am J Physiol Heart Circ Physiol. 2020 Nov 1;319(5):H1087-H1096. doi: 10.1152/ajpheart.00314.2020. Epub 2020 Sep 18.
TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension. 319: H1087-H1096, 2020. First published September 18, 2020; doi:10.1152/ajpheart.00314.2020.-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 -acetylcysteine 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. 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.
TIGAR 减少平滑肌细胞自噬以预防肺动脉高压。2020 年 9 月 18 日首次发表；doi:10.1152/ajpheart.00314.2020.-肺动脉高压（PAH）是一种难治性疾病。其预后仍然较差；因此，迫切需要建立新的治疗靶点。TP53 诱导的糖酵解和凋亡调节剂（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 被证明可抑制 PAH 的进展。因为抑制自噬和 ROS 已知可改善 PAH，所以我们研究了 TIGAR 对 PAH 进展的影响。我们比较了缺氧诱导的 PH 模型中 TIGAR 缺陷敲除（KO）和野生型（WT）小鼠的肺动脉高压（PH）发展情况。使用小干扰 RNA（siRNA）的人肺动脉平滑肌细胞（PASMCs）进行体外实验，以研究可能的分子机制。从右心室压力、右心室重量和死亡率的分析中，我们得出结论，TIGAR KO 小鼠的缺氧诱导 PH 发展明显高于 WT 小鼠。病理研究表明，TIGAR KO 小鼠的肺小动脉中层增厚和细胞增殖增加。TIGAR KO 小鼠的自噬和 ROS 活性也增加。siRNA 敲低 TIGAR 可增加细胞增殖和迁移，加剧自噬，并在缺氧时增加 ROS 的产生。TIGAR 敲低和缺氧暴露引起的 PASMCs 增殖和迁移被氯喹抑制自噬和乙酰半胱氨酸抑制 ROS 所减弱。TIGAR 通过抑制自噬和 ROS 抑制 PASMCs 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。
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剂（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 抑制 PASMCs 的增殖和迁移，从而改善缺氧诱导的 PH。TIGAR 将成为 PAH 的一个有前途的治疗靶点。
Zotero 插件