硫酸吲哚酚与小分子气体硫化氢在血管内皮细胞功能中的相互作用及分子机制-透析者心血管疾病的潜在治疗靶点

Maintenance hemodialysis (MHD) population is characterized by much higher prevalence and mortality of hypertension and other cardiovascular diseases than the general populations. To clear its mechanism is of great significance. Endogenous hydrogen sulfide (H2S) is a protecting gas in cardio-cerebro-vascular disease and its deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Studies on the mechanism are in the ascendant around the world. Past studies have shown that H2S levels are decreased significantly in hemodialysis patients through transcriptional deregulation of genes encoding for the H(2)S-producing enzymes, but the exact reason remains unknown. Our preliminary study showed for the first time that serum indoxyl sulfate (IS) leves were negatively associated with serum hydrogen sulfide concentrations among MHD patients, and IS played an important role in connections between H2S and MHD-related refractory hypertension. Futher experiments on cells found that IS induced a dose-dependent reduction of H2S in human umbilical vein endothelial(HUVEC), while low concentrations of H2S can alleviate IS- induced damage to HUVEC cell (HUVEC) with raised NO production and reduced cell apoptosis. Therefore, we hypothesized that IS can lower CSE expression through a certain signaling pathway, which might be an important reason for the lack of H2S and a high incidence of cardio-cerebro-vascular diseases. To clarify its molecular mechanisms, researches in cells and animals will be conducted to explore the exact influences and signal transduction between IS and CSE/H2S, and also the protective effects of exogenous H2S donor, which may provide a theoretical basis for the prevention of cardio-cerebro-vascular complications in MHD patients.

维持性血液透析（MHD）患者心脑血管疾病发病率是一般人群的二十倍，明确其机制意义重大。内源性硫化氢（H2S），心脑血管的保护气体，其合成减少常见于多种心脑血管疾病，对其机制的研究方兴未艾。既往研究显示MHD患者H2S水平显著下降，但机制不明。本课题前期研究首次发现MHD患者血清H2S水平与硫酸吲哚酚（IS）浓度呈负相关，且IS在H2S与MHD难治性高血压关系中有重要作用；细胞实验显示IS可剂量依赖性的减少脐静脉内皮细胞（HUVEC）H2S生成；低浓度H2S可改善IS对HUVEC的损伤，上调细胞NO生成，减轻细胞凋亡。因此，我们推测IS通过某信号途径下调CSE表达，是MHD患者缺乏H2S及心脑血管疾病高发的重要原因。为明确其分子机制，我们拟行细胞及动物实验深入观察IS对内源性H2S合成的影响及信号转导通路，以及外源性H2S供体的保护作用及分子机制，为防治MHD患者心脑血管疾病提供理论基础。

维持性血液透析（MHD）患者心脑血管疾病发病率是一般人群的20倍，明确其机制意义重大。内源性硫化氢（H2S）其合成减少常见于多种心脑血管疾病，对其机制的研究方兴未艾，既往研究显示MHD患者H2S水平显著下降，但机制不明。.本课题研究首次发现MHD患者血清H2S水平与硫酸吲哚酚（IS）浓度呈负相关，且IS在H2S与MHD难治性高血压关系中有重要作用；细胞实验显示IS可剂量依赖性的减少脐静脉内皮细胞（HUVEC）H2S生成；低浓度H2S可改善IS对HUVEC的损伤，上调细胞NO生成，减轻细胞凋亡。.在非透析CKD患者的研究发现，CKD患者血浆H2S水平显著低于健康对照组（4.20（2.98-9.40）vs 10.24（9.98~16.25）nmol/ml，P<0.01）。患者红细胞内硫血红蛋白（SHb）含量与肾小球滤过率（eGFR）呈正相关（ρ=0.406，P=0.029）；与血浆IS浓度呈负相关（ρ=-0.393，P=0.043）。CKD患者血浆碳氧血红蛋白（HbCO）和NO浓度显著低于健康对照组（P<0.01），CKD患者血浆H2S浓度与血浆HbCO浓度呈正相关（ρ=0.221，P=0.042）。此外，CKD患者H2S合成酶的底物同型半胱氨酸（Hcy）的血浆浓度显著高于健康对照（P<0.01）；其血浆水平随肾功能减退而进一步升高，CKD1-2期患者血Hcy含量显著低于CKD3-5期患者。VitB6作为H2S合成酶的辅因子，CKD患者血浆水平显著高于健康对照组。超声心动图检查发现CKD患者血浆H2S浓度与心脏左室射血分数（LVEF）呈负相关（ρ=-0.207，P=0.034）。血SHb含量与LVPWT呈正相关（ρ=0.437，P=0.020），与cTnT浓度呈负相关（ρ=-0.376，P=0.034）。.CKD患者血浆H2S水平较健康人显著降低，可能与肾功能减退、VitB6和HbCO水平显著降低等因素相关。H2S、CO等内源性小分子气体间相互影响，协同作用，并与某些影响心脑血管事件的因素如血HDL-C，LDL-C，LVEF，cTnT，血压有一定的关联；血液透析后患者血清硫化氢水平较透析前显著升高。

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