Lipopolysaccharide potentiates endothelin-1-induced proliferation of pulmonary arterial smooth muscle cells by upregulating TRPC channels
Lipopolysaccharide potentiates endothelin-1-induced proliferation of pulmonary arterial smooth muscle cells by upregulating TRPC channels
复制标题
脂多糖通过上调 TRPC 通道增强内皮素 1 诱导的肺动脉平滑肌细胞增殖
DOI：
10.1016/j.biopha.2016.04.055
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发表时间：
2016-08-01
影响因子：
7.5
通讯作者：
Qu, Jie-Ming
中科院分区：
文献类型：
--
作者：
Jiang, Hong-Ni;Zeng, Bo;Qu, Jie-Ming
脂多糖（LPS）和内皮素-1（ET-1）是脓毒症肺动脉高压的重要致病因子，但二者是否协同作用尚不清楚。我们发现，虽然LPS不改变大鼠肺动脉平滑肌细胞（PASMC）对ET-1的收缩反应，但它显著促进ET-1诱导的PASMC增殖。内皮素1（ET-1）诱导的PASMCs内Ca ~（2+）瞬变的测定表明，LPS显著增强瞬时受体电位经典（TRPC）通道介导的Ca ~（2+）内流。LPS不直接激活TRPC通道，而是选择性上调肺动脉TRPC 3和TRPC 4的表达。针对TRPC通道的小干扰RNA（siRNA）和化学阻断剂消除LPS诱导的PASMC增殖。LPS诱导的细胞增殖和TRPC表达是由Ca 2+依赖的钙调神经磷酸酶/NFAT信号通路介导的。我们认为阻断TRPC通道可能是控制内毒素暴露后肺动脉重构的有效策略。(C)2016 Elsevier Masson SAS。All rights reserved.
Lipopolysaccharide (LPS) and endothelin-1 (ET-1) are critical pathogenic factors in sepsis-induced pulmonary hypertension; however it is unknown whether they have a coordinated action in the pathogenesis of this disease. Here we found that although LPS did not change the contractility of rat pulmonary arterial smooth muscle cells (PASMCs) in response to ET-1, it significantly promoted ET-1-induced PASMC proliferation. Measurement of ET-1-evoked Ca2+ transients in PASMCs showed that LPS dramatically enhanced Ca2+ influx mediated by transient receptor potential canonical (TRPC) channels. LPS did not directly activate TRPC channels, instead it selectively upregulated the expression of TRPC3 and TRPC4 in pulmonary arteries. Small interfering RNA (siRNA) and chemical blockers against TRPC channels abolished LPS-induced PASMC proliferation. LPS-induced cell proliferation and TRPC expression was mediated by the Ca2+-dependent calcineurin/NFAT signaling pathway. We suggest that blocking TRPC channels could be an effective strategy in controlling pulmonary arterial remodeling after endotoxin exposure. (C) 2016 Elsevier Masson SAS. All rights reserved.