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      • Cathepsin K Activity Controls Injury-Related Vascular Repair in Mice

        Hu, Lina,Cheng, Xian Wu,Song, Haizhen,Inoue, Aiko,Jiang, Haiying,Li, Xiang,Shi, Guo-Ping,Kozawa, Eiji,Okumura, Kenji,Kuzuya, Masafumi American Heart Association, Inc. 2014 Hypertension Vol.63 No.3

        <P>Cathepsin K (CatK) is one of the most potent mammalian collagenases. We showed previously the increased expression of CatK in human and animal atherosclerotic lesions. Here, we hypothesized that ablation of CatK mitigates injury-induced neointimal hyperplasia. Male wild-type (CatK<SUP>+/+</SUP>) and CatK-deficient (CatK<SUP>−/−</SUP>) mice underwent ligation or a combination of ligation and polyethylene cuff-replacement injuries to the right common carotid artery just proximal to its bifurcation, and they were then processed for morphological and biochemical studies at specific time points. On operative day 28, CatK<SUP>−/−</SUP> significantly reduced neointimal formation and neovessel formation in both single- and combination-injured arteries compared with the Cat K<SUP>+/+</SUP> mice. At early time points, CatK<SUP>−/−</SUP> reduced the lesion macrophage contents and medial smooth muscle cell proliferation, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2, toll-like receptor-4, chemokine ligand-12, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. An aorta-explant assay revealed that smooth muscle cell movement was impaired in the CatK<SUP>−/−</SUP> mice compared with the CatK<SUP>+/+</SUP> mice. In addition, the smooth muscle cells and macrophages from CatK<SUP>−/−</SUP> mice had less invasive ability through a reconstituted basement membrane barrier. This vasculoprotective effect was mimicked by Cat inhibition with <I>trans</I>-epoxysuccinyl-L-leucylamido-{4-guanidino} butane (E64<I>d</I>). These results demonstrate an essential role of CatK in neointimal lesion formation in response to injury, possibly via the reduction of toll-like receptor-2/-4–mediated inflammation and smooth muscle cell proliferation, suggesting a novel therapeutic strategy for the control of endovascular treatment–related restenosis by regulating CatK activity.</P>

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        Increased Serum Cathepsin K in Patients with Coronary Artery Disease

        Xiang Li,Lan Cui,Yuzi Li,Jiyong Jin,Dehao Jin,Xiangshan Li,Yanna Rei,Haiying Jiang,Guangxian Zhao,Guang Yang,Enbo Zhu,Yongshan Nan,Xianwu Cheng 연세대학교의과대학 2014 Yonsei medical journal Vol.55 No.4

        Purpose: Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD). Materials and Methods: Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age-matched subjects served as controls. Results: The subjects’ serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterolwere measured. The patients with CAD had significantly higher serum cathepsinK levels compared to the controls (130.8±25.5 ng/mL vs. 86.9±25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1± 26.9 ng/mL vs. 102.6±12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs-CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01). Conclusion: These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD.

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