Carboxyl-Terminal Cleavage of Apolipoprotein A-I by Human Mast Cell Chymase Impairs Its Anti-Inflammatory Properties.

Autor:	Nguyen SD; 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.)., Maaninka K; 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.)., Lappalainen J; 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.)., Nurmi K; 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.)., Metso J; 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.)., Öörni K; 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.)., Navab M; 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.)., Fogelman AM; 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.)., Jauhiainen M; 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.)., Lee-Rueckert M; 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.)., Kovanen PT; 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.
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2016 Feb; Vol. 36 (2), pp. 274-84. Date of Electronic Publication: 2015 Dec 17.
DOI:	10.1161/ATVBAHA.115.306827
Abstrakt:	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. Approach and 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. (© 2015 The Authors.)
Databáze:	MEDLINE
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