ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension
ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension
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DOI：
10.1164/rccm.201703-0502oc
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发表时间：
2018-02-01
影响因子：
24.7
通讯作者：
Schermuly, Ralph T.
中科院分区：
文献类型：
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作者：
Budas, Grant R.;Boehm, Mario;Schermuly, Ralph T.
基本原理：肺动脉高压（PAH）的进展与肺血管和右心室（RV）的病理性重塑相关。氧化应激通过激活MAPKs驱动重塑过程目的：我们研究是否有药物抑制氧化还原敏感的顶端MAPK，ASK 1，（凋亡信号调节激酶1），可以阻止肺血管和RV重构的进展。将选择性口服ASK 1抑制剂GS-444217给予两种PAH临床前大鼠模型（野百合碱和Sugen/缺氧）、由肺动脉缩窄诱导的RV压力超负荷的小鼠模型和细胞模型。在PAH模型中，经口给予GS-444217可剂量依赖性降低肺动脉压并减少RV肥大。GS-444217的治疗效果与ASK 1磷酸化减少、肺动脉肌化减少和RV纤维化基因表达减少相关。重要的是，当GS-444217给药于已确诊疾病的动物时观察到疗效，并在孤立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。在细胞模型中，GS-444217减少了p38和JNK的磷酸化，在大鼠心肌细胞中通过腺病毒过表达ASK 1诱导c-Jun N-末端激酶（c-Jun N-terminal kinase），并减少来自PAH患者的原代小鼠心脏成纤维细胞和人肺外膜成纤维细胞的活化/迁移。在啮齿动物模型中，ASK 1抑制减少了肺血管和右心室的病理性重塑，并阻止了肺动脉高压的进展。这些临床前数据首次描述了ASK 1在PAH疾病发病机制中的因果作用。
Rationale: 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.Objectives: 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.Methods: 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.Measurements and Main Results: 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.Conclusions: 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.