Tags

Type your tag names separated by a space and hit enter

Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes.
Biochem Pharmacol. 2020 05; 175:113849.BP

Abstract

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.

Authors+Show Affiliations

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.Department of Obstetrics and Gynecology, Xuzhou Medical University Affiliated Hospital, Xuzhou 221006, Jiangsu, China.Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China.Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Department of Pharmacology, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. Electronic address: ywliu@xzhmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32059841

Citation

Liu, Yue, et al. "Thrombin/PAR-1 Activation Induces Endothelial Damages Via NLRP1 Inflammasome in Gestational Diabetes." Biochemical Pharmacology, vol. 175, 2020, p. 113849.
Liu Y, Tang ZZ, Zhang YM, et al. Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. Biochem Pharmacol. 2020;175:113849.
Liu, Y., Tang, Z. Z., Zhang, Y. M., Kong, L., Xiao, W. F., Ma, T. F., & Liu, Y. W. (2020). Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. Biochemical Pharmacology, 175, 113849. https://doi.org/10.1016/j.bcp.2020.113849
Liu Y, et al. Thrombin/PAR-1 Activation Induces Endothelial Damages Via NLRP1 Inflammasome in Gestational Diabetes. Biochem Pharmacol. 2020;175:113849. PubMed PMID: 32059841.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. AU - Liu,Yue, AU - Tang,Zhuang-Zhuang, AU - Zhang,Yu-Meng, AU - Kong,Li, AU - Xiao,Wei-Fen, AU - Ma,Teng-Fei, AU - Liu,Yao-Wu, Y1 - 2020/02/12/ PY - 2019/12/15/received PY - 2020/02/06/accepted PY - 2020/2/16/pubmed PY - 2020/10/30/medline PY - 2020/2/16/entrez KW - AGEs/RAGE axis KW - Endothelial injury KW - Gestational diabetes mellitus KW - NLRP1 inflammasome KW - Sarsasapogenin KW - thrombin/PAR-1 pathway SP - 113849 EP - 113849 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 175 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/32059841/Thrombin/PAR_1_activation_induces_endothelial_damages_via_NLRP1_inflammasome_in_gestational_diabetes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(20)30070-8 DB - PRIME DP - Unbound Medicine ER -