Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+channels
Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+channels
复制标题
DOI：
10.1073/pnas.1221997110
复制
发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Hou, Shangwei
中科院分区：
文献类型：
--
作者：
Hoshi, Toshinori;Wissuwa, Bianka;Hou, Shangwei
长链多不饱和omega-3脂肪酸，如二十二碳六烯酸(DHA)，在油性鱼类中大量存在，可能具有多种促进健康的作用，潜在地保护免疫、神经和心血管系统。然而，DHA所谓的健康促进作用背后的机制仍然很不清楚，部分原因是DHA的分子信号通路和效应器才刚刚开始被揭示。在血管平滑肌细胞中，大电导钙通道和电压激活钾(BK)通道提供重要的血管扩张作用。我们在这里报告了EC50类似于500 NM的DHA快速且可逆地激活由成孔的Slo1亚基和辅助亚基Beta 1组成的BK通道，使电流增加近20倍。DHA作用是在无细胞贴片中观察到的，不需要电压传感器激活或钙离子结合，但涉及离子传导门闭合构象的不稳定。DHA可降低麻醉野生型小鼠的血压，但不能降低Slo1基因敲除小鼠的血压。膳食补充剂中含有的DHA乙酯不能激活BK通道，拮抗DHA的兴奋作用。因此，SLO1 BK通道是长链omega-3脂肪酸的受体，这些脂肪酸不同于它们的乙酯衍生物，激活通道并降低血压。这一发现对于将omega-3脂肪酸用作普通公众的营养食品以及接受富含omega-3的配方奶粉的危重患者具有实际意义。
Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA), found abundantly in oily fish, may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems. However, the mechanisms underlying the purported health-promoting effects of DHA remain largely unclear, in part because molecular signaling pathways and effectors of DHA are only beginning to be revealed. In vascular smooth muscle cells, large-conductance Ca2+-and voltage-activated K+ (BK) channels provide a critical vasodilatory influence. We report here that DHA with an EC50 of similar to 500 nM rapidly and reversibly activates BK channels composed of the pore-forming Slo1 subunit and the auxiliary subunit beta 1, increasing currents by up to similar to 20-fold. The DHA action is observed in cell-free patches and does not require voltage-sensor activation or Ca2+ binding but involves destabilization of the closed conformation of the ion conduction gate. DHA lowers blood pressure in anesthetized wildtype but not in Slo1 knockout mice. DHA ethyl ester, contained in dietary supplements, fails to activate BK channels and antagonizes the stimulatory effect of DHA. Slo1 BK channels are thus receptors for long-chain omega-3 fatty acids, and these fatty acids-unlike their ethyl ester derivatives-activate the channels and lower blood pressure. This finding has practical implications for the use of omega-3 fatty acids as nutraceuticals for the general public and also for the critically ill receiving omega-3-enriched formulas.