FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice.

Autor: Yakala GK; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Cabrera-Fuentes HA; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.).; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.).; Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany (H.A.C.-F.).; Department of Microbiology, Kazan Federal University, Russian Federation (H.A.C.-F.).; Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Centro de Biotecnologia-FEMSA, Nuevo Leon, México (H.A.C.-F.)., Crespo-Avilan GE; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.).; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.)., Rattanasopa C; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.).; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.)., Burlacu A; Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania (A.B.)., George BL; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.)., Anand K; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Mayan DC; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Corlianò M; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Hernández-Reséndiz S; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.).; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.)., Wu Z; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Schwerk AMK; Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden (A.M.K.S., R.K.)., Tan ALJ; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Trigueros-Motos L; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Chèvre R; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Chua T; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.)., Kleemann R; Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden (A.M.K.S., R.K.).; Department of Vascular Surgery, Leiden University Medical Center, the Netherlands (R.K.)., Liehn EA; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.).; Institute of Molecular Cardiovascular Research, RWTH, Aachen, Germany (E.A.L.).; Human Genetic Laboratory, University of Medicine, Craiova, Romania (E.A.L.)., Hausenloy DJ; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.).; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.).; Yong Loo Lin School of Medicine, National University Singapore (D.J.H.).; The Hatter Cardiovascular Institute, University College London, United Kingdom (D.J.H.).; The National Institute of Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (D.J.H.).; Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom (D.J.H.)., Ghosh S; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.).; National Heart Research Institute, National Heart Centre Singapore (H.A.C.-F., G.E.C.-A., B.L.G., S.H.-R., E.A.L., D.J.H., S.G.)., Singaraja RR; From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.).
Jazyk: angličtina
Zdroj: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2019 Mar; Vol. 39 (3), pp. 387-401.
DOI: 10.1161/ATVBAHA.118.311903
Abstrakt: Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr -/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe -/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.
Databáze: MEDLINE