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TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension.
American Journal of Physiology-Heart and Circulatory Physiology ( IF 4.8 ) Pub Date : 2020-09-18 , DOI: 10.1152/ajpheart.00314.2020
Ryoetsu Yamanaka 1 , Atsushi Hoshino 1 , Kuniyoshi Fukai 1 , Ryota Urata 1 , Yoshito Minami 1 , Sakiko Honda 1 , Yohei Fushimura 1 , Daichi Hato 1 , Eri Iwai-Kanai 2 , Satoaki Matoba 1
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Background: 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 the PAH progression. Since inhibition of autophagy and ROS are known to improve PAH, we examined the effect of TIGAR on PAH progression. Methods: 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. Results: From analysis of right ventricular pressure, right heart weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in the WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation was increased in TIGAR KO mice. Autophagy and ROS activity was 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-acetylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. Conclusions: 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.

中文翻译:

TIGAR可减少平滑肌细胞自噬,以预防肺动脉高压。

背景:肺动脉高压(PAH)是一种难治性疾病。它的预后仍然很差。因此,迫切需要建立新的治疗靶标。TP53诱导的糖酵解和凋亡调节剂(TIGAR)是p53的下游靶标,并具有抑制自噬和活性氧(ROS)的功能。最近,显示p53抑制PAH进程。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。方法:我们使用缺氧诱导的PH模型比较了TIGAR缺陷敲除(KO)和野生型(WT)小鼠之间的肺动脉高压(PH)的发展。使用人类肺动脉平滑肌细胞(PASMC)进行体外实验,并使用小干扰RNA(siRNA)来研究可能的分子机制。结果:通过对右心室压力,右心重量和死亡率的分析,我们得出结论,TIGAR KO缺氧诱导的PH发育显着高于WT小鼠。病理研究表明,TIGAR KO小鼠的肺小动脉内侧增厚和细胞增殖增加。TIGAR KO小鼠的自噬和ROS活性也增加。siRNA对TIGAR的抑制作用增加了细胞的增殖和迁移,加剧了自噬,并且在缺氧期间增加了ROS的产生。氯喹的自噬抑制作用和N-乙酰半胱氨酸的ROS抑制作用减弱了TIGAR敲除和低氧暴露引起的PASMCs的增殖和迁移。结论:TIGAR通过抑制自噬和ROS抑制了PASMCs的增殖和迁移,因此,改善缺氧引起的PH。因此,TIGAR可能是PAH的有希望的治疗靶标。
更新日期:2020-09-20
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