Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarisation in pulmonary hypertension.
Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarisation in pulmonary hypertension.
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DOI：
10.1183/13993003.01814-2015
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Olschewski A
中科院分区：
文献类型：
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作者：
Nagaraj C;Tang B;Nagy BM;Papp R;Jain PP;Marsh LM;Meredith AL;Ghanim B;Klepetko W;Kwapiszewska G;Weir EK;Olschewski H;Olschewski A
ω-3脂肪酸如二十二碳六烯酸（DHA）对心脏的保护作用已得到证实，但DHA对肺动脉高压患者血管张力和压力的调节作用在很大程度上尚不清楚。由于DHA是K+通道的有效调节剂，我们假设DHA通过K+通道调节肺动脉平滑肌细胞（PASMCs）的膜电位，从而对肺血管张力和压力产生影响。我们发现，DHA引起原发人PASMCs中钙活化K+ (KCa)电流的剂量依赖性激活和肺动脉内皮依赖性松弛。KCa−/−(Kcnma1−/−)小鼠的血管舒张功能明显减弱。在体内，急性DHA可使慢性缺氧肺动脉高压动物模型右心室收缩压恢复到正常动物水平。有趣的是，在特发性肺动脉高压中，KCa通道及其亚基上调。DHA激活了这些人类PASMCs中的KCa通道，并使特发性肺动脉高压PASMCs的膜电位与来自健康供体的PASMCs的膜电位超极化。我们的研究结果表明，DHA激活PASMC - KCa通道，导致肺动脉高压的血管松弛。这种效应可能为先前描述的DHA在肺动脉高压中作为急性血管扩张剂的作用提供了分子解释。
Cardioprotective benefits of ω-3 fatty acids such as docosahexaenoic acid (DHA) are well established, but the regulatory effect of DHA on vascular tone and pressure in pulmonary hypertension is largely unknown. As DHA is a potent regulator of K+ channels, we hypothesised that DHA modulates the membrane potential of pulmonary artery smooth muscle cells (PASMCs) through K+ channels and thus exerts its effects on pulmonary vascular tone and pressure. We show that DHA caused dose-dependent activation of the calcium-activated K+ (KCa) current in primary human PASMCs and endothelium-dependent relaxation of pulmonary arteries. This vasodilation was significantly diminished in KCa−/− (Kcnma1−/−) mice. In vivo, acute DHA returned the right ventricular systolic pressure in the chronic hypoxia-induced pulmonary hypertension animal model to the level of normoxic animals. Interestingly, in idiopathic pulmonary arterial hypertension the KCa channels and their subunits were upregulated. DHA activated KCa channels in these human PASMCs and hyperpolarised the membrane potential of the idiopathic pulmonary arterial hypertension PASMCs to that of the PASMCs from healthy donors. Our findings indicate that DHA activates PASMC KCa channels leading to vasorelaxation in pulmonary hypertension. This effect might provide a molecular explanation for the previously undescribed role of DHA as an acute vasodilator in pulmonary hypertension.