Role of Cholesterol in the Regulation of Hydrogen Sulfide Signaling within the Vascular Endothelium.
Role of Cholesterol in the Regulation of Hydrogen Sulfide Signaling within the Vascular Endothelium.
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DOI：
10.3390/antiox11091680
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发表时间：
2022-08-28
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影响因子：
--
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H2S 是哺乳动物体内酶促产生的气体信号分子，产生 H2S 的酶在整个血管壁中表达。我们之前报道H2S诱导的血管舒张是通过瞬时受体电位阳离子通道亚家族V成员4（TRPV4）和大电导（BKCa）钾通道介导的；然而，该途径的调节因子尚未确定。先前的报告表明，膜胆固醇限制 TRPV4 和 BKCa 钾通道的活性。目前的研究检查了内皮细胞 (EC) 质膜 (PM) 胆固醇调节 H2S 诱导的血管舒张的能力。我们假设 EC PM 胆固醇会阻碍肠系膜大动脉中 H2S 介导的血管舒张。在加压的 U46619 预收缩肠系膜动脉中，使用甲基-β-环糊精 (MBCD, 100 µM) 降低大动脉中的 EC PM 胆固醇会增加 H2S 诱导的扩张 (NaHS 10, 100 µM)，但 MBCD 治疗对小动脉没有影响。 Enface 荧光显示，肠系膜大动脉中的 EC PM 胆固醇含量高于小动脉中的 EC PM 胆固醇含量。大动脉 MBCD 治疗后 NaHS 诱导的血管舒张被 TRPV4 和 BKCa 通道抑制剂（分别为 GSK219384A，300 nM 和伊贝里奥毒素，100 nM）阻断。肠系膜动脉横截面的免疫组织化学显示TRPV4和BKCa均存在于大动脉和小动脉的EC中。在小动脉的 EC PM 中补充胆固醇可以消除 NaHS 诱导的血管舒张，但胆固醇对映体表胆固醇则没有效果。邻近连接分析研究并未显示 EC PM 胆固醇含量与 TRPV4 和 BK 关联之间的相关性。总的来说，这些结果表明 EC PM 胆固醇通过影响 EC TRPV4 和 BKCa 通道来限制 H2S 诱导的血管舒张。
H2S is a gaseous signaling molecule enzymatically produced in mammals and H2S-producing enzymes are expressed throughout the vascular wall. We previously reported that H2S-induced vasodilation is mediated through transient receptor potential cation channel subfamily V member 4 (TRPV4) and large conductance (BKCa) potassium channels; however, regulators of this pathway have not been defined. Previous reports have shown that membrane cholesterol limits activity of TRPV4 and BKCa potassium channels. The current study examined the ability of endothelial cell (EC) plasma membrane (PM) cholesterol to regulate H2S-induced vasodilation. We hypothesized that EC PM cholesterol hinders H2S-mediated vasodilation in large mesenteric arteries. In pressurized, U46619 pre-constricted mesenteric arteries, decreasing EC PM cholesterol in large arteries using methyl-β-cyclodextrin (MBCD, 100 µM) increased H2S-induced dilation (NaHS 10, 100 µM) but MBCD treatment had no effect in small arteries. Enface fluorescence showed EC PM cholesterol content is higher in large mesenteric arteries than in smaller arteries. The NaHS-induced vasodilation following MBCD treatment in large arteries was blocked by TRPV4 and BKCa channel inhibitors (GSK219384A, 300 nM and iberiotoxin, 100 nM, respectively). Immunohistochemistry of mesenteric artery cross-sections show that TRPV4 and BKCa are both present in EC of large and small arteries. Cholesterol supplementation into EC PM of small arteries abolished NaHS-induced vasodilation but the cholesterol enantiomer, epicholesterol, had no effect. Proximity ligation assay studies did not show a correlation between EC PM cholesterol content and the association of TRPV4 and BK. Collectively, these results demonstrate that EC PM cholesterol limits H2S-induced vasodilation through effects on EC TRPV4 and BKCa channels.
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DOI：
10.1126/science.1162667
发表时间：
2008-10-24
期刊：
Science (New York, N.Y.)
影响因子：
--
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发表时间：
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