胎盘中硫化氢合成酶在妊娠期糖尿病发生和发展中的作用及其机制

Increased secretion of inflammatory factors by placenta a is critical to inflammatory response activation, insulin resistance of gestational diabetes mellitus (GDM) patients. We have found that both of placenta and maternal peripheral tissue expressed hydrogen sulfide synthase -- cystathionine-β-synthase(CBS), cystathionine-γ-lyase(CSE), 3-mercaptopyruvate sulfurtransferase(3-MST). In GDM placenta, hydrogen sulfide synthase were downregulated, NLRP3 inflammasome which mediated inflammatory response was upregulated; hydrogen sulfide synthase were downregulated, NLRP3 inflammasome was upregulated in maternal peripheral tissue exposed to high glucose. We are going to explorer the effect of hydrogen sulfide synthase on NLRP3 inflammasome in placenta. We will investigate whether knockdown or knockout of hydrogen sulfide synthase in placenta result in high blood glucose, insulin resistance, inflammatory response activation in placenta and maternal peripheral tissue; whether elevated blood glucose in pregnant mice result in decreased hydrogen sulfide synthase expression and inflammatory response activation in placenta and maternal peripheral tissues. We will also investigate the therapeutic effects of hydrogen sulfide sustained release agent and overexpression of placental hydrogen sulfide synthase in GDM. The present project will clarity the role and mechanism of hydrogen sulfide synthase in the genesis and development of GDM and explor novel therapeutic approach for GDM.

胎盘炎性因子分泌增多是导致妊娠期糖尿病（GDM）患者炎症反应激活、胰岛素抵抗的重要原因。我们前期研究表明胎盘及母体外周组织中均表达硫化氢合成酶--胱硫醚-β-合成酶（CBS）、胱硫醚-γ-裂解酶（CSE）、3-巯基丙酮酸硫基转移酶（3-MST），GDM胎盘中硫化氢合成酶表达减少、介导炎症反应的NLRP3炎性小体表达增多，高糖能够抑制母体外周组织中硫化氢合成酶表达、增加NLRP3炎性小体表达。我们将进一步研究胎盘中硫化氢合成酶对NLRP3炎性小体的调节作用，孕鼠胎盘中硫化氢合成酶敲低及敲除是否导致血糖升高、胰岛素抵抗、胎盘及母体外周组织中炎症反应激活，孕鼠血糖升高是否导致胎盘及母体外周组织中硫化氢合酶表达减少、炎症反应激活，硫化氢缓释剂及胎盘中硫化氢合成酶过表达是否能够治疗GDM等，以阐明胎盘中硫化氢合成酶在GDM发生、发展中的作用及机制并发现治疗GDM的新途径。

胎盘炎性因子分泌增多是导致妊娠期糖尿病（GDM）患者炎症反应激活、胰岛素抵抗的重要原因。我们前期研究表明GDM胎盘中硫化氢（H2S）合成酶硫化氢合成酶-胱硫醚-β-合成酶（CBS）及胱硫醚-γ-裂解酶（CSE）表达降低，介导炎症反应的NLRP3炎性小体表达增多，高糖能够抑制母体外周组织中硫化氢合成酶表达、增加NLRP3炎性小体表达。在此基础上，本项目通过一系列细胞实验、动物实验探究胎盘中H2S合成酶在GDM发病中的作用及机制。研究结果表明：（1）GDM胎盘中CBS、CSE表达降低与NLRP3、Caspase-1表达增加具有负相关关系；（2）H2S供体NaHS及前体L-半胱氨酸抑制胎盘滋养细胞中NLRP3、Caspase-1的表达及IL-1β、IL-18的释放；（3）敲低妊娠小鼠胎盘中CSE的表达后，母体胰岛素抵抗程度加重，胎盘组织中NLRP3、Caspase-1的表达增加；（4）高糖增加胎盘滋养细胞及脂肪细胞中NLRP3、Caspase-1的表达及IL-1β、IL-18的释放；H2S供体NaHS抑制高糖诱导胎盘滋养细胞及脂肪细胞中NLRP3、Caspase-1表达增加及IL-1β、IL-18释放增加。本项目初步揭示了胎盘中H2S合成酶表达降低与GDM发生及发展的关系，为今后阐明GDM的发病机制提供了研究基础，也为发现GDM新的治疗途径提供了思路。