Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis
Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis
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DOI：
10.1152/ajplung.00129.2014
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发表时间：
2015-03-15
影响因子：
4.9
通讯作者：
Mitani, Yoshihide
中科院分区：
文献类型：
--
作者：
Shinohara, Tsutomu;Sawada, Hirofumi;Mitani, Yoshihide
目前尚不清楚目前的疾病靶向治疗是否可以在组织学上逆转阻塞性肺血管病变，以及治疗的时机如何影响化合物的抗重塑作用。我们检验了一种新型内皮素受体拮抗剂马昔腾坦逆转大鼠闭塞性肺血管病（PVD）早期和/或晚期的假设。通过联合暴露于血管内皮生长因子受体抑制剂Sugen 5416和低压缺氧3周产生肺动脉高压（PAH）大鼠，在注射Sugen后3-5周（早期研究）或5-8周（晚期研究）期间分配接受马昔腾坦或溶剂。与溶媒给药PAH大鼠和给药开始前评价的PAH大鼠相比，马昔腾坦给药大鼠在早期研究中显示闭塞性病变比例降低，这一结果与右心室收缩压逆转以及右心室肥大和中壁厚度指数一致。在后期研究中，马昔腾坦改善但未逆转闭塞性病变的比例。尽管在两项研究中马昔腾坦均降低了Ki 67+病变的比例，但在早期研究中，马昔腾坦增加了裂解的半胱天冬酶3+病变的比例，并抑制了抗凋亡分子生存素的表达，但在晚期研究中则没有。总之，马昔腾坦可逆转大鼠早期而非晚期阻塞性PVD。这种逆转与生存素相关的细胞凋亡和增殖的PVD细胞的阻力的抑制。
It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3-5 wk (early study) or during 5-8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.