title: Carboxyl-Terminal Cleavage of Apolipoprotein A-I by Human Mast Cell Chymase Impairs Its Anti-Inflammatory Properties.
abstract: OBJECTIVE
  Apolipoprotein A-I (apoA-I) has been shown to possess several atheroprotective functions, including inhibition of inflammation. Protease-secreting activated mast cells reside in human atherosclerotic lesions. Here we investigated the effects of the neutral proteases released by activated mast cells on the anti-inflammatory properties of apoA-I.
  
  
  RESULTS
  Activation of human mast cells triggered the release of granule-associated proteases chymase, tryptase, cathepsin G, carboxypeptidase A, and granzyme B. Among them, chymase cleaved apoA-I with the greatest efficiency and generated C-terminally truncated apoA-I, which failed to bind with high affinity to human coronary artery endothelial cells. In tumor necrosis factor-α-activated human coronary artery endothelial cells, the chymase-cleaved apoA-I was unable to suppress nuclear factor-κB-dependent upregulation of vascular cell adhesion molecule-1 (VCAM-1) and to block THP-1 cells from adhering to and transmigrating across the human coronary artery endothelial cells. Chymase-cleaved apoA-I also had an impaired ability to downregulate the expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-8 in lipopolysaccharide-activated GM-CSF (granulocyte-macrophage colony-stimulating factor)- and M-CSF (macrophage colony-stimulating factor)-differentiated human macrophage foam cells and to inhibit reactive oxygen species formation in PMA (phorbol 12-myristate 13-acetate)-activated human neutrophils. Importantly, chymase-cleaved apoA-I showed reduced ability to inhibit lipopolysaccharide-induced inflammation in vivo in mice. Treatment with chymase blocked the ability of the apoA-I mimetic peptide L-4F, but not of the protease-resistant D-4F, to inhibit proinflammatory gene expression in activated human coronary artery endothelial cells and macrophage foam cells and to prevent reactive oxygen species formation in activated neutrophils.
  
  
  CONCLUSIONS
  The findings identify C-terminal cleavage of apoA-I by human mast cell chymase as a novel mechanism leading to loss of its anti-inflammatory functions. When targeting inflamed protease-rich atherosclerotic lesions with apoA-I, infusions of protease-resistant apoA-I might be the appropriate approach.
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Su Duy
authors.initials: SD
authors.lastname: Nguyen
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Katariina
authors.initials: K
authors.lastname: Maaninka
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Jani
authors.initials: J
authors.lastname: Lappalainen
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Katariina
authors.initials: K
authors.lastname: Nurmi
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Katariina
authors.initials: K
authors.lastname: Öörni
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.).
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee-Rueckert
authors.affiliation: From the Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland (S.D.N., K.M., J.L., K.N., K.Ö., M.L.-R., P.T.K.); National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum Helsinki, Helsinki, Finland (J.M., M.J.); and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F.). petri.kovanen@wri.fi.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism* / Q000494:pharmacology; D050197:Atherosclerosis / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D053818:Chymases / Q000378:metabolism*; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D016207:Cytokines; C465468:D-4F peptide; D018836:Inflammation Mediators; C472885:L-4F peptide; D016328:NF-kappa B; D010455:Peptides; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D002784:Cholesterol; D053818:Chymases
keywords: apolipoprotein A-I; carboxyl-terminal cleavage; chymase; endothelial cells; inflammatory; mast cell; proteases