title: Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE-/- Mice.
abstract: Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response.
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Marjo M P C
authors.initials: MM
authors.lastname: Donners
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Lili
authors.initials: L
authors.lastname: Bai
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Suzanne P M
authors.initials: SP
authors.lastname: Lutgens
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: Wijnands
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Marlbrough Street, Bristol, BS2 8HW, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, NRB-742, 77 Avenue Louis Pasteur, Boston, Massachusetts, 02115, United States of America.
authors.forename: Cong-Lin
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Kitty B J M
authors.initials: KB
authors.lastname: Cleutjens
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, NRB-742, 77 Avenue Louis Pasteur, Boston, Massachusetts, 02115, United States of America.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D056657:Cathepsin K / Q000378:metabolism*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012039:Regional Blood Flow; D066253:Vascular Remodeling
chemical_list: D001057:Apolipoproteins E; D056657:Cathepsin K