Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Pharmacy, The Second Hospital of Shandong University, Jinan, 250033, China.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China.
Arch Biochem Biophys. 2022 Jul 15;723:109267. doi: 10.1016/j.abb.2022.109267. Epub 2022 Apr 26.
Right ventricular (RV) remodeling is a major feature of pulmonary arterial hypertension (PAH). Vascular peroxidase 1 (VPO1) is reported to participate in the process of PAH. This study aims to explore whether VPO1 contributes to hypoxia-induced cardiac hypertrophy and the underlying mechanisms. SD rats were exposure to continuous hypoxia (10% O) for 3 weeks, which showed RV hypertrophy (increases in the ratio of RV weight to tibia length, cardiac cell size and hypertrophic markers), concomitant with upregulation of VPO1, elevation in hypochlorous acid (HOCl) production and ERK phosphorylation. In hypoxia (3% O)-induced hypertrophic H9c2 cells, similar characteristics of cardiac hypertrophy to that of hypoxia-treated rats were observed. Administration of VPO1 siRNA or NaHS (the HOCl inhibitor) suppressed HOCl production, ERK phosphorylation, and cardiac hypertrophy. Replacement of hypoxia with NaClO (exogenous HOCl) could also induce cardiac cell hypertrophy and activate ERK signaling pathway. In addition, hypoxia-induced cardiac hypertrophy could be blocked by PD98059 (the ERK-specific inhibitor). Based on these observations, we conclude that VPO1 promotes RV remodeling in PAH rats through catalyzing HOCl production, leading to the activation of ERK signaling. Thus, VPO1 may have the potential as a therapeutic target for PAH.
右心室（RV）重构是肺动脉高压（PAH）的主要特征。据报道，血管过氧化物酶 1（VPO1）参与 PAH 的发生过程。本研究旨在探讨 VPO1 是否有助于缺氧诱导的心肌肥厚及其潜在机制。SD 大鼠连续暴露于 10% O2 的缺氧环境中 3 周，结果显示 RV 肥厚（RV 重量与胫骨长度之比增加、心肌细胞增大和肥大标志物上调），同时 VPO1 上调、次氯酸（HOCl）生成和 ERK 磷酸化增加。在缺氧（3% O2）诱导的肥厚 H9c2 细胞中，观察到与缺氧处理大鼠相似的心肌肥厚特征。给予 VPO1 siRNA 或 NaHS（HOCl 抑制剂）可抑制 HOCl 生成、ERK 磷酸化和心肌肥厚。用 NaClO（外源性 HOCl）替代缺氧也可诱导心肌细胞肥大并激活 ERK 信号通路。此外，PD98059（ERK 特异性抑制剂）可阻断缺氧诱导的心肌肥厚。基于这些观察结果，我们得出结论，VPO1 通过催化 HOCl 生成促进 PAH 大鼠的 RV 重构，从而激活 ERK 信号通路。因此，VPO1 可能成为 PAH 的潜在治疗靶点。
