Chai Qiang, Lu Tong, Wang Xaio-Li, Lee Hon-Chi
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA,
Pflugers Arch. 2015 Feb;467(2):329-40. doi: 10.1007/s00424-014-1526-y. Epub 2014 May 6.
Hydrogen sulfide has emerged as an important endothelium-dependent vasodilator, but its role in shear stress-mediated dilation of coronary arteries is unclear. We examined the role of H2S on shear stress-mediated dilation of isolated mouse coronary arteries. In these vessels, Na2S produced concentration-dependent dilation, which was significantly inhibited by iberiotoxin and by 4-aminopyridine. In addition, BK and Kv currents in mouse coronary smooth muscle cells were directly activated by Na2S, suggesting that H2S produced vasodilation through BK and Kv channel activation. Using a pressure servo controller system, freshly isolated mouse coronary arteries were subjected to physiological levels of shear stress (1 to 25 dynes/cm(2)) and produced graded dilatory responses, but such effects were diminished in the presence of 100 μM Na2S. Pre-incubation with the cystathionine γ-lyase inhibitor, D,L-propargylglycine (PPG), resulted in a paradoxical augmentation of shear stress-mediated vasodilation. However, in the presence of L-NAME or in coronary arteries from eNOS knockout mice, PPG inhibited shear stress-mediated vasodilation, suggesting an interaction between NO and H2S signaling. Na2S inhibited eNOS activity in cultured mouse aortic endothelial cells and reduced the level of phospho-eNOS(serine 1177). These results suggest that both NO and H2S are important shear stress-mediated vasodilators in mouse coronary arteries but there is a complex interaction between these two signaling pathways that results in paradoxical vasoconstrictive effects of H2S through inhibition of NO generation.
硫化氢已成为一种重要的内皮依赖性血管舒张剂，但其在剪切应力介导的冠状动脉舒张中的作用尚不清楚。我们研究了硫化氢对离体小鼠冠状动脉剪切应力介导的舒张作用。在这些血管中，硫化钠产生浓度依赖性舒张，这种舒张被iberiotoxin和4-氨基吡啶显著抑制。此外，硫化钠直接激活小鼠冠状动脉平滑肌细胞中的BK和Kv电流，表明硫化氢通过激活BK和Kv通道产生血管舒张。使用压力伺服控制器系统，对新鲜分离的小鼠冠状动脉施加生理水平的剪切应力（1至25达因/平方厘米），并产生分级舒张反应，但在存在100μM硫化钠的情况下，这种作用减弱。用胱硫醚γ-裂解酶抑制剂D，L-炔丙基甘氨酸（PPG）预孵育导致剪切应力介导的血管舒张出现反常增强。然而，在存在L-NAME的情况下或在来自eNOS基因敲除小鼠的冠状动脉中，PPG抑制剪切应力介导的血管舒张，表明NO和硫化氢信号之间存在相互作用。硫化钠抑制培养的小鼠主动脉内皮细胞中的eNOS活性，并降低磷酸化eNOS（丝氨酸1177）水平。这些结果表明，NO和硫化氢都是小鼠冠状动脉中剪切应力介导的重要血管舒张剂，但这两种信号通路之间存在复杂的相互作用，导致硫化氢通过抑制NO生成而产生反常的血管收缩作用。
