Genetic knockout and pharmacologic inhibition of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension.
Genetic knockout and pharmacologic inhibition of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension.
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NCX1 的基因敲除和药物抑制可减轻缺氧引起的肺动脉高压。
DOI：
10.1016/j.bbrc.2020.06.045
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Iwamoto T.
中科院分区：
文献类型：
--
作者：
1.Nagata A;Tagashira H;Kita S;Kita T;Nakajima N;Abe K;Iwasaki A;Iwamoto T.
Na+/Ca~(2+)交换器-1(NCX1)是一种双向转运蛋白，受膜电位和Na~+、Ca~(2+)跨膜梯度控制。血管平滑肌NCX1在细胞内钙稳态和钙信号转导中起重要作用。我们发现NCX1在慢性低氧(10%O2持续4周)小鼠的肺动脉中表达上调。因此，我们利用NCX1基因杂合子(NCX1+/−)小鼠(NCX1表达减少一半)和NCX1特异性抑制剂SEA0400，研究了NCX1在缺氧性肺动脉高压中的病理生理作用。与野生型小鼠相比，NCX1+/−小鼠表现出低氧诱导的肺动脉高压的减轻和右室(RV)肥厚。此外，通过渗透压泵连续给野生型小鼠注射SEA0400(0.5 mg/kg/d，连续4周)可显著抑制低氧所致的PAH和肺血管肌化，但对RV肥大有轻微的抑制作用。这些结果表明，NCX1的上调参与了低氧诱导的PAH的发生，提示抑制NCX1可能是治疗PAH的一种新途径。
The Na+/Ca2+exchanger type-1 (NCX1) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na+and Ca2+. Vascular smooth muscle NCX1 plays an important role in intracellular Ca2+homeostasis and Ca2+signaling. We found that NCX1 was upregulated in the pulmonary arteries of mice exposed to chronic hypoxia (10% O2for 4 weeks). Hence, we investigated the pathophysiological role of NCX1 in hypoxia-induced pulmonary arterial hypertension (PAH), using NCX1-heterozygous (NCX1+/−) mice, in which NCX1 expression is reduced by half, and SEA0400, a specific NCX1 inhibitor. NCX1+/−mice exhibited attenuation of hypoxia-induced PAH and right ventricular (RV) hypertrophy compared with wild-type mice. Furthermore, continuous administration of SEA0400 (0.5 mg/kg/day for 4 weeks) to wild-type mice by osmotic pumps significantly suppressed hypoxia-induced PAH and pulmonary vessel muscularization, with a slight reduction in RV hypertrophy. These findings indicate that the upregulation of NCX1 contributes to the development of hypoxia-induced PAH, suggesting that NCX1 inhibition might be a novel approach for the treatment of PAH.
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影响因子：
4.8
作者：
Wakimoto, K;Kobayashi, K;Komuro, I
通讯作者：
Komuro, I
影响因子：
5.5
作者：
Zhang, Shen;Dong, Hui;Yuan, Jason X. -J.
通讯作者：
Yuan, Jason X. -J.
DOI：
10.1073/pnas.0405908101
发表时间：
2004-09-21
影响因子：
11.1
作者：
Yu, Y;Fantozzi, L;Yuan, JXJ
通讯作者：
Yuan, JXJ
影响因子：
20.1
作者：
Dierick, France;Hery, Tiphaine;Nadaud, Sophie
通讯作者：
Nadaud, Sophie