Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction.
Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction.
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DOI：
10.1093/cvr/cvn349
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发表时间：
2009-05-01
影响因子：
10.8
通讯作者：
Perez-Vizcaino F
中科院分区：
文献类型：
--
作者：
Cogolludo A;Moreno L;Frazziano G;Moral-Sanz J;Menendez C;Castañeda J;González C;Villamor E;Perez-Vizcaino F
缺氧性肺血管收缩（HPV）的机制尚未完全确定。本研究的目的是确定蛋白激酶C β（PKC β）和中性鞘磷脂酶（nSMase）在HPV中的作用。用免疫细胞化学法测定神经酰胺含量，用膜片钳技术记录肺动脉平滑肌细胞（PASMC）电压门控钾通道（KV）电流。收缩反应进行了分析，在大鼠肺动脉安装在一个金属丝myograph。在麻醉开胸大鼠中记录肺压。蛋白质和mRNA的表达分别通过Western blot和RT-PCR检测。我们发现，缺氧增加神经酰胺含量在PASMC这是废除抑制nSM酶，但不是酸性鞘磷脂酶（aSM酶）。在离体肺动脉中，通过抑制PKC β或nSMase而不是aSMase，可强烈地减少缺氧诱导的血管收缩反应和KV电流的抑制。nSMase抑制剂GW 4869在体内预防HPV。通过外源性添加细菌Smase和神经酰胺来模仿对缺氧的血管收缩反应。nSMase 2 mRNA在肺动脉中的表达是肠系膜动脉的10倍。在肠系膜动脉，缺氧未能增加神经酰胺，但外源性SMase引起的收缩反应。nSM酶衍生的神经酰胺产生和PKC β的激活是急性HPV信号级联中的早期和必要事件。
The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV. Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of KV currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response. nSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV.
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DOI：
10.1152/ajplung.2001.280.5.l888
发表时间：
2001-05-01
影响因子：
4.9
作者：
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通讯作者：
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影响因子：
20.1
作者：
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发表时间：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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作者：
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影响因子：
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