Wen Ji-Yue, Wang Mei, Li Ya-Nan, Jiang Hui-Hui, Sun Xuan-Jun, Chen Zhi-Wu
Department of Pharmacology, Anhui Medical University, Hefei, China.
Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, China.
Front Neurol. 2018 Oct 19;9:779. doi: 10.3389/fneur.2018.00779. eCollection 2018.
This study was undertaken to demonstrate the vascular protection of exogenous and endogenous hydrogen sulfide (HS) on cerebral ischemia/reperfusion (I/R) injury. The effect of HS on cerebrovascular dysfunction in middle cerebral artery (MCA) and neuronal damage were measured after cerebral I/R induced by transient middle cerebral artery occlusion (MCAO) in cystathionine c-lyase (CSE) knockdown and wild-type rats. The effect of sodium hydrosulfide (NaHS, donor of exogenous HS), L-cysteine (L-Cys, substrate of endogenous HS), and endothelium cells on the responses of isolated MCA derived from non-ischemic rats was also evaluated to assess the underlying mechanism of HS-mediate cerebral vasodilation. The results revealed that the contraction and dilation of MCA profoundly decreased after cerebral I/R. The vascular dysfunction became more grievous in CSE knockdown rats than in wild-type rats. Interestingly, this vascular dysfunction was significantly alleviated by NaHS supplementation. Moreover, both NaHS and L-cysteine could induce remarkable relaxation in the isolated MCA, which was eliminated by co-application of potassium channel blockers ChTx and Apamin, or endothelial removal. By contrast, adding endothelium cells cultured together with ACh into the luminal perfusate could mimic non-NO and non-PGI relaxation in endothelium-denuded MCA, once CSE was knocked down from endothelium cells, and its effect on vasorelaxation was abolished. Furthermore, the indexes of neuronal injury were measured after cerebral I/R to confirm the neuroprotection of HS, and we found that the neurological scores, cerebral infarction volume, brain water content, malondialdehyde content, and serum lactate dehydrogenase activity (a marker of cellular membrane integrity) were significantly higher in CSE knockdown rats than in normal control rats. It is not surprising that NaHS could alleviate the cerebral injury. These findings revealed that HS has a protective effect on cerebral I/R injury via its upregulation of the endothelium-dependent contraction and dilation function of cerebral vessels, which may be related to activating potassium channel.
本研究旨在证明外源性和内源性硫化氢（HS）对脑缺血/再灌注（I/R）损伤的血管保护作用。在胱硫醚γ-裂解酶（CSE）基因敲除大鼠和野生型大鼠中，通过短暂大脑中动脉闭塞（MCAO）诱导脑I/R后，检测HS对大脑中动脉（MCA）脑血管功能障碍和神经元损伤的影响。还评估了硫氢化钠（NaHS，外源性HS供体）、L-半胱氨酸（L-Cys，内源性HS底物）和内皮细胞对来自非缺血大鼠的离体MCA反应的影响,以评估HS介导脑血管舒张的潜在机制。结果显示，脑I/R后MCA的收缩和舒张功能显著降低。CSE基因敲除大鼠的血管功能障碍比野生型大鼠更严重。有趣的是，补充NaHS可显著减轻这种血管功能障碍。此外，NaHS和L-半胱氨酸均可使离体MCA产生显著舒张，而钾通道阻滞剂ChTx和蜂毒明肽共同应用或去除内皮可消除这种舒张作用。相反，一旦从内皮细胞中敲除CSE，将培养的内皮细胞与乙酰胆碱一起添加到管腔灌注液中，可模拟内皮剥脱的MCA中的非一氧化氮（NO）和非前列环素（PGI）介导的舒张，且其对血管舒张的作用消失。此外，在脑I/R后测量神经元损伤指标以证实HS的神经保护作用，我们发现CSE基因敲除大鼠的神经学评分、脑梗死体积、脑含水量、丙二醛含量和血清乳酸脱氢酶活性（细胞膜完整性标志物）显著高于正常对照大鼠。NaHS能减轻脑损伤不足为奇。这些发现表明，HS通过上调脑血管内皮依赖性收缩和舒张功能对脑I/R损伤具有保护作用，这可能与激活钾通道有关。
