缺氧(环境)
下调和上调
TRPC公司
化学
肺动脉高压
TRPC1型
右心室肥大
安倍生坦
药理学
内分泌学
体内
内科学
医学
生物
受体
瞬时受体电位通道
生物化学
内皮素受体
氧气
波生坦
有机化学
生物技术
基因
作者
Yong-Liang Jiang,Yumin Zhou,Gongyong Peng,Nian Liu,Heshen Tian,Dan Pan,Lei Liu,Xing Yang,Chao Li,Wen Li,Ling Chen,Pixin Ran,Aiguo Dai
标识
DOI:10.1016/j.biocel.2018.09.010
摘要
This study aimed to investigate the effects of topotecan (TPT) on the hypoxia-induced pulmonary arterial hypertension (PAH) in a rat model, and to explore the underlying mechanism. The experiments were carried out in vitro using rat PASMCs and in vivo using a rat model of hypoxia-induced PAH. TPT significantly suppressed the hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression both in pulmonary arterial smooth muscle cells (PASMCs) from normal rats and in pulmonary arteries from PAH model rats. Furthermore, TPT effectively inhibited intracellular Ca2+ concentration ([Ca2+]i) change (Ca2+ influx) in PASMCs from both normal rats and PAH model rats. Importantly, TPT treatment significantly inhibited the hypoxia-induced proliferation, migration and a contractile-to-synthetic phenotypic switching of normal rat PASMCs in vitro, where the effect was abrogated by overexpression of TRPC1/4/6. Furthermore, TPT administration potently attenuated the hypoxia-induced PAH-associated pulmonary arteriolar remodeling in PAH model rats, as evidenced by amelioration of elevated hemodynamic parameters, and enhanced right ventricle hypertrophy and wall thickening. TPT ameliorates the hypoxia-induced pulmonary vascular remodeling in PAH, and the mechanism is associated with TPT-mediated inhibition of hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression, Ca2+ influx, and PASMCs proliferation.
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