title: Inhibition of extracellular cyclophilins with cyclosporine analog and development of atherosclerosis in apolipoprotein E-deficient mice.
abstract: Cyclophilins exert both intracellular and extracellular activities related to immune responses and inflammation, which have been implicated in pathogenesis of atherosclerosis. Pan-inhibition of cyclophilins has both pro- and antiatherosclerotic properties, but specific contributions of extracellular and intracellular cyclophilins to these effects have not been characterized. Here, using selective inhibitor of extracellular cyclophilins, we investigated the role of these molecules in atherosclerosis. Apolipoprotein E-null mice fed a high-fat diet received intraperitoneal injections every second day of either vehicle or two analogs of cyclosporine A (CsA): [Melle](4)-CsA (NIM811), a nonimmunosupressive cell-permeable inhibitor of both intracellular and extracellular cyclophilins; and [(4R)-4-[(6-carboxy-1H-benzo[d]imidazol-2-yl)-methyl]-4-methyl-l-threonine](1)-CsA (MM284), cell-impermeable analog only inhibiting extracellular cyclophilins. Development of atherosclerosis and composition of plaques in aorta and innominate artery were studied. Both analogs increased abundance and cross-sectional size of the atherosclerotic plaques in aorta but did not affect development of atherosclerosis in innominate artery. Neither compound affected abundance of macrophages and amount of vascular cell adhesion molecule-1 or nitrotyrosine in the plaques of both arteries. Both compounds reduced the amount of collagen in innominate artery without affecting abundance of collagen in aortic sinus. MM284, but not NIM811, significantly reduced plasma concentration of tumor necrosis factor-α (TNFα); neither compound affected plasma concentrations of interleukin (IL)-6, IL-10 or monocyte chemoattractant protein-1. Ratio between different populations of immune cells in blood or isolated from lymph nodes and spleen as well as plasma lipoprotein profile were unaffected by both compounds. In conclusion, selective inhibition of extracellular cyclophilins reduced TNFα levels in plasma but increased atherosclerosis.
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.).
authors: Michael
authors: M
authors: Ditiatkovski
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.).
authors: Vijaya N L V
authors: VN
authors: Neelisetti
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.).
authors: Huanhuan L
authors: HL
authors: Cui
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.).
authors: Miroslav
authors: M
authors: Malesevic
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.).
authors: Gunter
authors: G
authors: Fischer
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.).
authors: Michael
authors: M
authors: Bukrinsky
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.D., V.N.L.V.N., H.L.C., D.S.); Department of Biochemistry, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany (M.M.); Max Planck Institute for Biophysical Chemistry, Gottingen, Germany (G.F.); and Department of Microbiology, and Immunology and Tropical Medicine, George Washington University, Washington, DC (M.B.) Dmitri.Sviridov@bakeridi.edu.au.
authors: Dmitri
authors: D
authors: Sviridov
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D050197:Atherosclerosis / Q000139:chemically induced* / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D003524:Cyclosporins / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D003524:Cyclosporins; D016207:Cytokines; D007166:Immunosuppressive Agents; D008074:Lipoproteins; C000599101:cyclosporine A, 4-((6-carboxy-1H-benzo(d)imidazol-2-yl)methyl)-4-methylthreonine)(1)-; D021983:Cyclophilins