Although clinical treatment has significant progress, acute pulmonary embolism is still a common disease with high morbidity and mortality. Janus Kinase 3, a member of JAK family, has been demonstrated to promote smooth muscle cell proliferation through STAT3. In this work, we explored the effect of JANEX-1 (a specific Janus Kinase 3 inhibitor) on platelet-derived growth factor (PDGF)-induced proliferation-related molecules in pulmonary artery smooth muscle cells (PVSMCs) in vitro and assessed the therapeutic potential of Janus Kinase 3 for vascular remodeling in acute pulmonary embolism mice. The results revealed that Janus Kinase 3 was overexpressed and active in PDGF-induced PVSMCs and acute pulmonary embolism mice, compared to a low expression in normal conditions. JANEX-1, blocking Janus Kinase 3 expression or activity, reduced Janus Kinase 3/STAT3 signaling pathway, VEGF expression, FAK activation, and PDGF-induced proliferation of PVSMCs, while overexpression of VEGF or FAK induced PVSMCs proliferation and resisted the negative effects of JANEX-1. Moreover, JANEX-1 improved right ventricular systolic pressure, survival and lung damage in acute pulmonary embolism-mice, and inhibited the thrombus-induced intimal hyperplasia and the expression of α-SMA, VEGF, and FAK activation under neointimal smooth muscle cells of acute pulmonary embolism mice. In conclusion, the data suggest that JANEX-1 exerts protective effects by inhibiting PVSMCs proliferation and vascular remodeling post-acute pulmonary embolism, in part through Janus Kinase 3/STAT3 signaling pathway-mediated VEGF expression and FAK activation. The data are helpful to elucidate the pharmacological mechanism and potential therapeutic effect of JANEX-1 in APE.

Impact statement

Accumulating evidence suggests that vascular remodeling due to immoderate proliferation and migration of SMCs is a common process occurring in APE. In this work, we tried to find a breakthrough in the pathological mechanism to alleviate the prognosis of APE by improving SMCs proliferation and explored the effect of JANEX-1 on PDGF-induced proliferation-related molecules in PVSMCs and assessed the therapeutic potential of JAK3 for vascular remodeling in APE mice. We demonstrated that JANEX-1, blocking JAK3 expression or activity, reduced JAK3/STAT3 signaling pathway, VEGF expression and FAK activation, and PDGF-induced proliferation of PVSMCs. Moreover, JANEX-1 inhibited the thrombus-induced intimal hyperplasia and the expression of VEGF and FAK activation in neointimal SMCs of APE mice. The data are helpful to elucidate the pharmacological mechanism and potential therapeutic effect of JANEX-1 in APE.

中文翻译：

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JANEX-1 通过肺动脉平滑肌细胞中的 VEGF 和 FAK 改善急性肺栓塞。

尽管临床治疗取得了重大进展，但急性肺栓塞仍是高发病率和高死亡率的常见疾病。Janus Kinase 3 是 JAK 家族的成员，已被证明可通过 STAT3 促进平滑肌细胞增殖。在这项工作中，我们探索JANEX-1对血小板衍生的生长因子（特定的Janus激酶3抑制剂）（PDGF）在肺动脉诱导增殖相关分子平滑的效果肌细胞（PVSMCs）体外并评估了 Janus Kinase 3 对急性肺栓塞小鼠血管重塑的治疗潜力。结果表明，与正常条件下的低表达相比，Janus 激酶 3 在 PDGF 诱导的 PVSMC 和急性肺栓塞小鼠中过度表达并具有活性。JANEX-1，阻断 Janus Kinase 3 表达或活性，降低 Janus Kinase 3/STAT3 信号通路、VEGF 表达、FAK 激活和 PDGF 诱导的 PVSMCs 增殖，而过表达 VEGF 或 FAK 诱导 PVSMCs 增殖并抵抗JANEX-1。此外，JANEX-1 改善急性肺栓塞小鼠的右心室收缩压、存活率和肺损伤，并抑制血栓引起的内膜增生和 α-SMA、VEGF、和急性肺栓塞小鼠新生内膜平滑肌细胞下的 FAK 活化。总之，数据表明 JANEX-1 通过抑制 PVSMC 增殖和急性肺栓塞后血管重塑发挥保护作用，部分是通过 Janus 激酶 3/STAT3 信号通路介导的 VEGF 表达和 FAK 激活。该数据有助于阐明JANEX-1在APE中的药理机制和潜在治疗作用。

影响陈述

越来越多的证据表明，由于 SMC 过度增殖和迁移导致的血管重塑是 APE 中常见的过程。在这项工作中，我们试图通过改善 SMCs 增殖来寻找减轻 APE 预后的病理机制的突破，并探讨 JANEX-1 对 PVSMCs 中 PDGF 诱导的增殖相关分子的影响，并评估 JAK3 的治疗潜力。 APE 小鼠的血管重塑。我们证明 JANEX-1 阻断 JAK3 表达或活性，减少 JAK3/STAT3 信号通路、VEGF 表达和 FAK 激活，以及 PDGF 诱导的 PVSMC 增殖。此外，JANEX-1 抑制血栓诱导的内膜增生以及 APE 小鼠新生内膜 SMC 中 VEGF 和 FAK 的表达。