Proteasome inhibitor bortezomib prevents proliferation and migration of pulmonary arterial smooth muscle cells

Yi‐Ching Liu, Yu‐Hsin Tseng, Yu‐Hsin Kuan, Lin‐Yen Wang, Shang‐En Huang, Siao‐Ping Tsai, Jwu‐Lai Yeh, Jong‐Hau Hsu
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Abstract

Pulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)‐approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti‐proliferative and anti‐migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet‐derived growth factor (PDGF)‐BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS‐, Ang II‐ and PDGF‐BB‐induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF‐BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down‐regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH.
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蛋白酶体抑制剂硼替佐米能防止肺动脉平滑肌细胞增殖和迁移
肺血管重塑是肺动脉高压(PAH)的一个关键病理过程,其特点是肺动脉平滑肌细胞(PASMC)增殖和迁移失控。硼替佐米(BTZ)是美国食品药品管理局(FDA)批准用于多发性骨髓瘤治疗的第一种蛋白酶体抑制剂。最近,有新的证据显示其具有逆转 PAH 的作用,尽管其机制尚不十分清楚。本研究首先通过胎牛血清(FBS)、血管紧张素II(Ang II)和血小板衍生生长因子(PDGF)-BB等不同诱导剂检测了BTZ对PASMCs的抗增殖和抗迁移作用,然后研究了包括细胞活性氧(ROS)和线粒体ROS在内的潜在机制,最后检测了ERK和Akt的信号转导。我们的研究结果表明,BTZ 可抑制 FBS、Ang II 和 PDGF-BB 诱导的增殖和迁移,同时减少细胞 ROS 和线粒体 ROS 的产生。此外,BTZ 还能抑制 Ang II 和 PDGF-BB 诱导的 ERK 和 Akt 磷酸化。这项研究表明,BTZ 可阻止 PASMCs 的增殖和迁移,而增殖和迁移可能是通过减少 ROS 的产生以及下调 ERK 和 Akt 来实现的。因此,蛋白酶体抑制可以成为治疗 PAH 的一个新的药物靶点。
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