Ihab Abd-Elrahman1, Karen Meir1, Hisanori Kosuge1, Yael Ben-Nun1, Tommy Weiss Sadan1, Chen Rubinstein1, Yaacov Samet1, Michael V McConnell1, Galia Blum2. 1. From the Institute of Drug Research, The School of Pharmacy, The Faculty of Medicine, The Hebrew University, Jerusalem, Israel (I.A.-E., Y.B.-N., T.W.S., G.B.); Department of Pathology (K.M.) and Department of Vascular Surgery (C.R., Y.S.), Hadassah Medical Center, Jerusalem, 9112001, Israel; and Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA (H.K., M.V.M.). 2. From the Institute of Drug Research, The School of Pharmacy, The Faculty of Medicine, The Hebrew University, Jerusalem, Israel (I.A.-E., Y.B.-N., T.W.S., G.B.); Department of Pathology (K.M.) and Department of Vascular Surgery (C.R., Y.S.), Hadassah Medical Center, Jerusalem, 9112001, Israel; and Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA (H.K., M.V.M.). galiabl@ekmd.huji.ac.il.
Abstract
BACKGROUND AND PURPOSE: Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo. METHODS: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes. RESULTS: Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU). CONCLUSIONS: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high-risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease.
BACKGROUND AND PURPOSE:Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo. METHODS: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes. RESULTS:Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU). CONCLUSIONS: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high-risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease.
Authors: Kelton A Schleyer; Ben Fetrow; Peter Zannes Fatland; Jun Liu; Maya Chaaban; Biwu Ma; Lina Cui Journal: ChemMedChem Date: 2021-01-15 Impact factor: 3.466
Authors: Ihab Abd-Elrahman; Hisanori Kosuge; Tommy Wises Sadan; Yael Ben-Nun; Karen Meir; Chen Rubinstein; Matthew Bogyo; Michael V McConnell; Galia Blum Journal: PLoS One Date: 2016-08-17 Impact factor: 3.240
Authors: Charles Preston Neff; Shaikh M Atif; Eric C Logue; Janet Siebert; Carsten Görg; James Lavelle; Suzanne Fiorillo; Homer Twigg; Thomas B Campbell; Andrew P Fontenot; Brent E Palmer Journal: J Immunol Date: 2020-09-14 Impact factor: 5.422