Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl 3 model

• Published in: Cellular and molecular life sciences : CMLS 2024-05, Vol.81 (1), p.205
• Main Authors: Jin, Xueying, Yue, Xueling, Huang, Zhe, Meng, Xiangkun, Xu, Shengnan, Wu, Yuna, Wan, Ying, Inoue, Aiko, Narisawa, Megumi, Hu, Lina, Shi, Guo-Ping, Umegaki, Hiroyuki, Murohara, Toyoaki, Lei, Yanna, Kuzuya, Masafumi, Cheng, Xian Wu
• Format: Article
• Language: English
• Subjects: ADAMTS13 Protein - genetics; ADAMTS13 Protein - metabolism; Animals; Apoptosis; Cathepsin K - genetics; Cathepsin K - metabolism; Chlorides - metabolism; Disease Models, Animal; Ferric Compounds; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Stress, Psychological - complications; Stress, Psychological - metabolism; Thrombosis - metabolism; Thrombosis - pathology; Transcription Factor HES-1 - genetics; Transcription Factor HES-1 - metabolism
• ISSN: 1420-9071
• DOI: 10.1007/s00018-024-05240-0

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