Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension
Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension
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DOI：
10.1124/jpet.116.237933
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Paralkar, Vishwas
中科院分区：
文献类型：
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作者：
Aiello, Robert J.;Bourassa, Patricia-Ann;Paralkar, Vishwas
肺动脉高压（PAH）是一种进行性疾病，定义为肺动脉压慢性升高，伴有广泛的肺血管重塑和血管周围炎症，特征为巨噬细胞、淋巴细胞、树突状细胞和肥大细胞的积聚。虽然疾病的确切病因尚不清楚，但临床和临床前数据强烈暗示5-羟色胺（5-HT）在该过程中的作用。在这里，我们研究了色氨酸羟化酶1（TPH 1），外周5-HT生物合成的限速酶，在两个临床前肺动脉高压（PH）模型，野百合碱（MCT）大鼠和semaxanib（SUGEN，Medinoah，苏州，中国）-缺氧大鼠的药理学抑制的慢性效应。在两种PH模型中，乙基（S）-8-（2-氨基-6-（（R）-1-（2-氨基-6-（（R）-1-（三氟甲基）苯基）氨基）氨基）苯甲酸）（5-氯-[1，19-联苯]-2-基）-2，2，2-三氟乙氧基）嘧啶-4-基）-2，8-二氮杂螺[4.5]癸烷-3-甲酸乙酯和（S）-8-（三氟甲基）苯甲酸乙酯。（2-氨基-6-（（R）-1-（2-氨基-6-（（R）-1-（三氟甲基）苯基）氨基）氨基）苯甲酸）（39，49-二甲基-3-（3-甲基-1H-吡唑-1-基）-[1，19-联苯]-4-基）-2，2，2-三氟乙氧基）嘧啶-4-基）-2，8-二氮杂螺[4.5]癸烷-3-羧酸酯，具有纳摩尔体外效力的新型口服活性TPH 1抑制剂，以剂量依赖性方式降低血清、肠道和肺5-HT水平，并显著降低雄性大鼠的肺动脉压、肺血管壁厚度和闭塞。在MCT大鼠模型中，肺5-HT的减少与组胺水平和肥大细胞数量的减少显着相关（P < 0.001，r（2）= 0.88）。相比之下，批准用于治疗PAH的血管扩张剂安立生坦和他达拉非均不能降低肥大细胞数量或5-HT水平，在治疗血管重塑方面也不如TPH 1抑制剂有效。当与安立生坦联合给药时，TPH 1抑制剂对肺血管重塑和压力显示出累加效应。这些数据表明，除了减少血管重塑外，TPH 1抑制还具有减少与PH相关的血管周围肥大细胞积聚的额外益处。
Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,19-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(39,49-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,19-biphenyl]-4-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P < 0.001, r(2) = 0.88). In contrast, neither ambrisentan nor tadalafil, which are vasodilators approved for the treatment of PAH, reduced mast cell number or 5-HT levels, nor were they as effective in treating the vascular remodeling as were the TPH1 inhibitors. When administered in combination with ambrisentan, the TPH1 inhibitors showed an additive effect on pulmonary vascular remodeling and pressures. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH.