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首页> 外文期刊>Biochemical Pharmacology >Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes
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Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes

机译：凝血酶/ pAR-1激活通过在妊娠期糖尿病中通过NLRP1炎性内皮损伤诱导内皮损伤

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Gestational diabetes mellitus (GDM) is associated with an increased risk of progressing to type 2 DM and cardiovascular disease; however, the pathogenesis is still poorly understood. This study was to investigate roles of thrombin and its receptor protease-activated receptor 1 (PAR-1) and NLRP1 inflammasome in endothelial injury in GDM condition. Umbilical cord and plasma of GDM patients and high glucose (HG) cultured human umbilical vein endothelial cells (HUVECs) were used to examine the pathological changes of these pathways. Meanwhile, ameliorative effects and potential mechanisms of a natural product sarsasapogenin (Sar) were investigated in HUVECs. Thrombin/PAR-1 pathway, advanced glycation endproducts (AGEs) and their receptor (RAGE) axis, and the nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) inflammasome were activated in GDM condition and HG-cultured HUVECs, accompanied by endothelial injury (decreased cell viability and increased lactate dehydrogenase release). Nevertheless, thrombin inhibition or PAR-1 antagonism caused decreases in AGEs formation and RAGE expression in HG-cultured HUVECs, while AGEs inhibition or RAGE antagonism declined PAR-1 expression not thrombin activity. Furthermore, thrombin inhibition or PAR-1 antagonism restrained NLRP1 inflammasome activation in HG-cultured HUVECs; meanwhile, NLRP1 expression and interleukin 18 levels were remarkably reduced in HG-cultured HUVECs after PAR-1 knockdown. Interestingly, Sar co-treatment could suppress thrombin/PAR-1 pathway, NLRP1 inflammasome, and AGEs/RAGE axis. Together, endothelial damages in GDM were likely due to enhanced interaction between AGEs/RAGE axis and thrombin/PAR-1 pathway, followed by NLRP1 inflammasome activation. Moreover, Sar may act as a protective agent against endothelial injury in chronic HG condition.
机译：妊娠期糖尿病（GDM）与进展到2 DM和心血管疾病的风险增加有关;然而，发病机制仍然明白很差。该研究是探讨凝血酶及其受体蛋白酶活化受体1（PAR-1）和NLRP1炎症在GDM条件下的内皮损伤中的作用。使用GDM患者和高葡萄糖（HG）培养的人脐静脉内皮细胞（HUVECS）的脐带和血浆用于检查这些途径的病理变化。同时，研究了Huvecs的自然产物Sarsasapoolsin（SAR）的改进效果和潜在机制。凝血酶/ pAR-1途径，先进的糖化封端（年龄）及其受体（RAGE）轴，以及核苷酸结合结构域和含有亮氨酸富含的含有蛋白质1（NLRP1）炎症组在GDM条件下，HG培养的HUVECS活化，伴有内皮损伤（降低细胞活力和增加的乳酸脱氢酶释放）。然而，凝血酶抑制或PAR-1对拮抗作用引起的，在HG培养的HUVEC中的形成和愤怒表达中引起的，而年龄抑制或愤怒拮抗作用下降，表达1不是凝血酶活性。此外，凝血酶抑制或PAR-1拮抗剂在HG培养的HUVEC中受到NLRP1炎症组织活化;同时，在PAR-1敲低后，在Hg培养的Huvecs中，NLRP1表达和白细胞介素18水平显着降低。有趣的是，SAR共同治疗可以抑制凝血酶/ pAR-1途径，NLRP1炎症和年龄/愤怒轴。在一起，GDM中的内皮损伤很可能是由于年龄/愤怒轴和凝血酶/β1-1途径之间的增强的相互作用，其次是NLRP1炎症组活化。此外，SAR可以作为慢性HG条件下对内皮损伤的保护剂。

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