The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats.
The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats.
复制标题
选择性PGI2受体激动剂selexipag可以改善SUGEN 5416/缺氧诱导的大鼠肺动脉高压。
DOI：
10.1371/journal.pone.0240692
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Kuwano K
中科院分区：
文献类型：
--
作者：
Honda Y;Kosugi K;Fuchikami C;Kuramoto K;Numakura Y;Kuwano K
肺动脉高压（PAH）是一种致死性疾病，其特征是由于血管张力增加和血管闭塞导致肺动脉压力进行性增加。内源性血管扩张剂前列环素及其类似物用作PAH的治疗剂。然而，其对闭塞性血管重塑的药理学作用尚未阐明。司来帕格是一种最近获批的口服选择性前列环素受体激动剂，具有非前列腺素类结构。在本研究中，我们在Sprague-Dawley和Fischer大鼠模型中研究了司来帕格对慢性重度PAH病理学的药理学作用，其中PAH是通过联合注射血管内皮生长因子受体拮抗剂Sugen 5416和暴露于缺氧（SuHx）诱导的。司来帕格经口给药3周可显著改善Sprague-Dawley SuHx大鼠的右心室收缩压和右心室（RV）肥大。司来帕格降低了闭塞性病变肺血管的比例和肺动脉的中壁厚度，对应于重塑血管中Ki-67阳性细胞数量减少和1型胶原蛋白表达减少。对患有SuHx诱导PAH的Fischer大鼠给予司来帕格可降低RV肥大和RV衰竭引起的死亡率。这些作用可能基于司来帕格对肺血管的强效前列环素受体激动作用。司来帕格已在全球获批用于PAH的临床治疗。认为前列环素受体激动剂对PAH病理学多个方面的这些有益作用有助于PAH患者的临床结局。
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH.
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影响因子：
7.3
作者：
Asaki, Tetsuo;Kuwano, Keiichi;Clozel, Martine
通讯作者：
Clozel, Martine
影响因子：
24.3
作者：
Gomez-Arroyo, Jose;Sakagami, Masahiro;Voelkel, Norbert F.
通讯作者：
Voelkel, Norbert F.
DOI：
10.1164/rccm.201607-1515pp
发表时间：
2017-03-01
影响因子：
24.7
作者：
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通讯作者：
Humbert, Marc
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影响因子：
5.4
作者：
Liu, Panpan;Yan, Shuangquan;Huang, Xiaoying
通讯作者：
Huang, Xiaoying
影响因子：
3.5
作者：
Nakamura, Akio;Yamada, Tetsuhiro;Asaki, Tetsuo
通讯作者：
Asaki, Tetsuo