1 Gilead Sciences, Foster City, California.
2 Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Giessen, Germany; and.
Am J Respir Crit Care Med. 2018 Feb 1;197(3):373-385. doi: 10.1164/rccm.201703-0502OC.
Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis.
We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling.
A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models.
Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH.
ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.
肺动脉高压（PAH）的进展与肺血管和右心室（RV）的病理性重塑有关。氧化应激通过激活丝裂原活化蛋白激酶（MAPKs）驱动重塑过程，MAPKs 刺激细胞凋亡、炎症和纤维化。
我们研究了抑制氧化还原敏感的顶端 MAPK（凋亡信号调节激酶 1，ASK1）是否可以阻止肺血管和 RV 重塑的进展。
使用一种选择性的、可口服的 ASK1 抑制剂，GS-444217，对两种 PAH 的临床前大鼠模型（野百合碱和 Sugen/hypoxia）、肺动脉结扎诱导的 RV 压力超负荷的小鼠模型以及细胞模型进行了给药。
GS-444217 的口服给药剂量依赖性地降低了肺动脉压，并降低了 PAH 模型中的 RV 肥大。GS-444217 的治疗效果与 ASK1 磷酸化减少、肺动脉肌化减少和 RV 纤维化基因表达减少有关。重要的是，当 GS-444217 给予已患有疾病的动物时，以及在孤立 RV 压力超负荷模型中直接减少心脏纤维化和改善心脏功能时，也观察到了疗效。在细胞模型中，GS-444217 减少了腺病毒过表达 ASK1 诱导的大鼠心肌细胞中 p38 和 JNK（c-Jun N-末端激酶）的磷酸化，并减少了原代小鼠心肌成纤维细胞和源自 PAH 患者的人肺外膜成纤维细胞的激活/迁移。
ASK1 抑制减少了肺血管和右心室的病理性重塑，并阻止了啮齿动物模型中肺动脉高压的进展。这些临床前数据首次描述了 ASK1 在 PAH 发病机制中的因果作用。
