Increased dipeptidyl peptidase-4 accelerates chronic stress-related thrombosis in a mouse carotid artery model. Issue 8 (August 2020)

• Record Type: Journal Article
• Authors: Jin, Xianglan; Jin, Chunzi; Nakamura, Kae; Jin, Tiefeng; Xin, Minglong; Wan, Ying; Yue, Xueling; Jin, Shengyu; Wang, Hailong; Inoue, Aiko; Nan, Yongshan; Lin, Zhenhua; Kuzuya, Masafumi; Cheng, Xian Wu
• Is Part Of: Journal of hypertension. Volume 38:Issue 8(2020:Aug.)
• Publication Date: 2020-08
• Subjects: carotid artery -- chronic stress -- endothelial injury -- oxidative stress -- thrombosis; Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000002418
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: Exposure to chronic psychosocial stress is a risk factor for metabolic cardiovascular disorders. Given that dipeptidyl peptidase-4 (DPP-4) has an important role in human pathobiology, we investigated the role of DPP-4 in stress-related thrombosis in mice, focusing on oxidative stress and the von Willebrand factor (vWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). Methods and results: Male mice randomly assigned to nonstress and 2-week immobilized-stress groups underwent iron chloride3 (FeCl3 )-induced carotid artery thrombosis surgery for morphological and biochemical studies at specific times. On day 14 post-stress/surgery, stress had enhanced the lengths and weights of arterial thrombi, with alterations of plasma DPP-4, plasminogen activation inhibitor-1 and ADAMTS13. The stressed mice had increased levels of vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1, gp91phox, p22phox, matrix metalloproteinase-2 (MMP-2), MMP-9, cathepsins S and K mRNAs and/or proteins, and reduced levels of endothelial nitric oxide synthase, catalase and superoxide dismutase-1 mRNAs and/or proteins. Stress also accelerated arterial endothelial cell damage. The DPP-4 inhibitor anagliptin ameliorated the stress-induced targeted molecular and morphological changes and thrombosis. In vitro, DPP-4 inhibition also mitigated the alterations in the targeted ADAMTS13 and other oxidative and inflammatory molecules in human umbilical vein endothelial cells in response to H2 O2 . Conclusion: DPP-4 inhibition appeared to improve the FeCl3 -induced thrombosis in mice that received stress, possibly via the improvement of ADAMTS13 and oxidative stress, suggesting that DPP-4 could become a novel therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disorders. Abstract : Supplemental Digital Content is available in the text