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.

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.

• Authors: Su Duy Nguyen, Katariina Maaninka, Jani Lappalainen, Katariina Nurmi, Jari Metso, Katariina Öörni, Mohamad Navab, Alan M Fogelman, Matti Jauhiainen, Miriam Lee-Rueckert, Petri T Kovanen
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 36 Issue 2 Pg. 274-84 (Feb 2016) ISSN: 1524-4636 [Electronic] United States
• PMID: 26681753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors.

Chemical References

• APOA1 protein, human
• Apolipoprotein A-I
• Cytokines
• D-4F peptide
• Inflammation Mediators
• L-4F peptide
• NF-kappa B
• Peptides
• Reactive Oxygen Species
• Vascular Cell Adhesion Molecule-1
• Cholesterol
• Chymases

Topics

• Apolipoprotein A-I (metabolism, pharmacology)
• Atherosclerosis (enzymology, immunology, prevention & control)
• Cell Adhesion
• Cell Line, Tumor
• Cholesterol (metabolism)
• Chymases (metabolism)
• Coculture Techniques
• Cytokines (metabolism)
• Endothelial Cells (drug effects, immunology, metabolism)
• Foam Cells (immunology, metabolism)
• Humans
• Inflammation (enzymology, immunology, prevention & control)
• Inflammation Mediators (metabolism)
• Mast Cells (drug effects, enzymology, immunology)
• NF-kappa B (metabolism)
• Neutrophil Activation
• Neutrophils (immunology, metabolism)
• Peptides (pharmacology)
• Protein Structure, Tertiary
• Proteolysis
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Transendothelial and Transepithelial Migration
• Vascular Cell Adhesion Molecule-1 (metabolism)