Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model

• DOI: 10.1007/s00018-024-05240-0
• Publication Date: 2024-05-04T06:01:26Z
• Authors: Xueying Jin; Xueling Yue; Zhe Huang; Xiangkun Meng; Shengnan Xu; Yuna Wu; Ying Wan; Aiko Inoue; Megumi Narisawa; Lina Hu; Guo-Ping Shi; Hiroyuki Umegaki; Toyoaki Murohara; Yanna Lei; Masafumi Kuzuya; Xian Wu Cheng
• Keywords: Cathepsin K

Abstract Background Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, we investigated whether CTSK involved stress-related thrombosis, focusing on serum-induced endothelial apoptosis. Methods results Eight-week-old wild-type male mice (CTSK +/+ ) randomly divided non-stress 3-week restraint groups received left carotid artery iron chloride3 (FeCl 3 )-induced thrombosis injury biological morphological evaluations at specific timepoints. On day 21 post-stress/injury, had enhanced arterial thrombi weights lengths, addition harmful alterations plasma ADAMTS13, von Willebrand factor, plasminogen activation inhibitor-1, plus injured-artery loss protein/mRNA expression. increased levels injured cleaved Notch1, Hes1, caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16 IN4A , p22phox, gp91 phox intracellular adhesion molecule-1, TNF-α, MCP-1, TLR-4 proteins and/or genes. Pharmacological genetic inhibitions ameliorated stress-induced thrombus formation observed molecular changes. In cultured HUVECs, overexpression silencing respectively mitigated stressed-serum- H 2 O -induced apoptosis associated with apoptosis-related protein Recombinant human degraded γ-secretase substrate dose-dependent manor activated Notch1 Hes1 upregulation. Conclusions appeared contribute subjected FeCl stress, possibly via modulation vascular inflammation, oxidative production apoptosis, suggesting that could be an effective therapeutic target CPS-related events patients CCVDs.