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

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Duy Nguyen , S , Maaninka , K , Lappalainen , J , Nurmi , K , Metso , J , Oorni , K , Navab , M , Fogelman , A M , Jauhiainen , M , Lee-Rueckert , M & Kovanen , P T 2016 , ' Carboxyl-Terminal Cleavage of Apolipoprotein A-I by Human Mast Cell Chymase Impairs Its Anti-Inflammatory Properties ' , Arteriosclerosis, Thrombosis, and Vascular Biology , vol. 36 , no. 2 , pp. 274-284 . https://doi.org/10.1161/ATVBAHA.115.306827

Title: Carboxyl-Terminal Cleavage of Apolipoprotein A-I by Human Mast Cell Chymase Impairs Its Anti-Inflammatory Properties
Author: Duy Nguyen, Su; Maaninka, Katariina; Lappalainen, Jani; Nurmi, Katariina; Metso, Jari; Oorni, Katariina; Navab, Mohamad; Fogelman, Alan M.; Jauhiainen, Matti; Lee-Rueckert, Miriam; Kovanen, Petri T.
Contributor: University of Helsinki, Biomedicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Clinicum
Date: 2016-02
Language: eng
Number of pages: 11
Belongs to series: Arteriosclerosis, Thrombosis, and Vascular Biology
ISSN: 1079-5642
URI: http://hdl.handle.net/10138/229682
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. 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--activated human coronary artery endothelial cells, the chymase-cleaved apoA-I was unable to suppress nuclear factor-B-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-, interleukin-1, 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.
Subject: apolipoprotein A-I
carboxyl-terminal cleavage
chymase
endothelial cells
inflammatory
mast cell
proteases
HIGH-DENSITY-LIPOPROTEIN
HUMAN APOA-I
CHOLESTEROL EFFLUX
ENDOTHELIAL-CELLS
PROTEOLYTIC INACTIVATION
GENE-EXPRESSION
FOAM CELLS
TNF-ALPHA
HDL
BINDING
3111 Biomedicine
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