Cathepsin G activity lowers plasma LDL and reduces atherosclerosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Wang, Jing^1,2  Sjoeberg, Sara^1,2  Tang, Ting-Ting³  Oorni, Katariina⁴  Wu, Wenxue^1,2  Liu, Conglin^1,2  Secco, Blandine^1,2  Tia, Viviane^1,2  Sukhova, Galina K.^1,2  Fernandes, Cleverson^1,2  Lesner, Adam⁵  Kovanen, Petri T.⁴  Libby, Peter^1,2  Cheng, Xiang³  Shi, Guo-Ping^1,2 

[1] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Inst Cardiol, Wuhan 430022, Peoples R China

[4] Wihuri Res Inst, Helsinki 00290, Finland

[5] Univ Gdansk, Dept Chem, PL-80952 Gdansk, Poland

关键词: Cathepsin G;    Atherosclerosis;    Low-density lipoprotein;    Elastin;    Angiotensin-II;   

DOI  :  10.1016/j.bbadis.2014.07.026

来源: Elsevier

【 摘 要 】

Cathepsin G (CatG), a serine protease present in mast cells and neutrophils, can produce angiotensin-II (Ang-II) and degrade elastin. Here we demonstrate increased CatG expression in smooth muscle cells (SMCs), endothelial cells (ECs), macrophages, and T cells from human atherosclerotic lesions. In low-density lipoprotein (LDL) receptor-deficient (Ldlr(-/-)) mice, the absence of CatG reduces arterial wall elastin degradation and attenuates early atherosclerosis when mice consume a Western diet for 3 months. When mice consume this diet for 6 months, however, CatG deficiency exacerbates atherosclerosis in aortic arch without affecting lesion inflammatory cell content or extracellular matrix accumulation, but raises plasma total cholesterol and LDL levels without affecting high-density lipoprotein (HDL) or triglyceride levels. Patients with atherosclerosis also have significantly reduced plasma CatG levels that correlate inversely with total cholesterol (r = -0.535, P < 0.0001) and LDL cholesterol (r = -0.559, P < 0.0001), but not with HDL cholesterol (P = 0.901) or triglycerides (P = 0.186). Such inverse correlations with total cholesterol (r = -0.504, P < 0.0001) and LDL cholesterol (r = -0.502, P < 0.0001) remain significant after adjusting for lipid lowering treatments among this patient population. Human CatG degrades purified human LDL, but not HDL This study suggests that CatG promotes early atherogenesis through its elastinolytic activity, but suppresses late progression of atherosclerosis by degrading LDL without affecting HDL or triglycerides. (C) 2014 Elsevier B.V. All rights reserved.

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