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二十二碳六烯酸激活大鼠冠状动脉平滑肌细胞中BK通道的机制

Mechanisms of BK Channel Activation by Docosahexaenoic Acid in Rat Coronary Arterial Smooth Muscle Cells.

作者信息

Qian Ling-Ling, Sun Man-Qing, Wang Ru-Xing, Lu Tong, Wu Ying, Dang Shi-Peng, Tang Xu, Ji Yuan, Liu Xiao-Yu, Zhao Xiao-Xi, Wang Wen, Chai Qiang, Pan Min, Yi Fu, Zhang Dai-Min, Lee Hon-Chi

机构信息

Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical UniversityWuxi, China.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States.

出版信息

Front Pharmacol. 2018 Mar 27;9:223. doi: 10.3389/fphar.2018.00223. eCollection 2018.

DOI:10.3389/fphar.2018.00223
PMID:29636681
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5881017/
Abstract

Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques. We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of <1 μM, DHA activated whole-cell BK currents with an EC of 0.24 ± 0.05 μM and the activation effects were abolished by pre-incubation with SKF525A (10 μM), a cytochrome P450 (CYP) epoxygenase inhibitor, suggesting the role of DHA-epoxide. High concentrations of DHA (1-10 μM) activated whole-cell BK currents with an EC of 2.38 ± 0.22 μM and the activation effects were unaltered by pre-incubation with SKF525A. Single channel studies showed that the open probabilities of BK channels were unchanged in the presence of low concentrations of DHA, while significantly increased with high concentrations of DHA. In addition, DHA induced a dose-dependent increase in cytosolic calcium concentrations with an EC of 0.037 ± 0.01 μM via phospholipase C (PLC)-inositol triphosphate (IP)-Ca signal pathway, and inhibition of this pathway reduced DHA-induced BK activation. These results suggest that DHA can activate BK channels by multiple mechanisms. Low concentration DHA-induced BK channel activation is mediated through CYP epoxygenase metabolites, while high concentration DHA can directly activate BK channels. In addition, DHA at low and high concentrations can both activate BK channels by elevated cytosolic calcium through the PLC-IP-Ca signal pathway.

摘要

已知二十二碳六烯酸（DHA）可激活血管大电导钙激活钾（BK）通道，并对心血管系统具有保护作用。然而，DHA激活BK通道的潜在机制仍不清楚。在本研究中，我们使用膜片钳技术，通过检测不同浓度的DHA对新鲜分离的大鼠冠状动脉平滑肌细胞（CASMCs）中BK通道的影响来确定这些机制。我们发现BK通道是大鼠CASMCs中被DHA激活的主要钾电流，并且DHA对BK通道的影响具有浓度依赖性，呈双峰分布。在浓度<1μM时，DHA激活全细胞BK电流，其半数有效浓度（EC）为0.24±0.05μM，且预先用细胞色素P450（CYP）环氧合酶抑制剂SKF525A（10μM）孵育可消除激活作用，提示DHA-环氧化物的作用。高浓度的DHA（1 - 10μM）激活全细胞BK电流，其EC为2.38±0.22μM，预先用SKF525A孵育不会改变激活作用。单通道研究表明，在低浓度DHA存在时，BK通道的开放概率不变，而在高浓度DHA时显著增加。此外，DHA通过磷脂酶C（PLC）-肌醇三磷酸（IP）-钙信号通路诱导胞质钙浓度呈剂量依赖性增加，其EC为0.037±0.01μM，抑制该信号通路可降低DHA诱导的BK通道激活。这些结果表明，DHA可通过多种机制激活BK通道。低浓度DHA诱导的BK通道激活是通过CYP环氧合酶代谢产物介导的，而高浓度DHA可直接激活BK通道。此外，低浓度和高浓度的DHA均可通过PLC-IP-钙信号通路升高胞质钙浓度来激活BK通道。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/5881017/7eba476dc12d/fphar-09-00223-g007.jpg
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