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Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):526-32. doi: 10.1161/ATVBAHA.113.302544. Epub 2013 Dec 26.

Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress.

Author information

1
From the Edward A. Doisy Department of Biochemistry and Molecular Biology and the Center for Cardiovascular Research, Saint Louis University School of Medicine, MO.

Abstract

OBJECTIVE:

Myeloperoxidase-enriched monocytes play important roles in inflammatory disease, such as atherosclerosis. We previously demonstrated that α-chlorofatty aldehydes are produced as a result of plasmalogen targeting by myeloperoxidase-derived hypochlorous acid in activated monocytes. Here, we show α-chlorofatty acid (α-ClFA), a stable metabolite of α-chlorofatty aldehydes, accumulates in activated monocytes and mediates the molecular effects of α-ClFA on monocytes/macrophages.

APPROACH AND RESULTS:

Liquid chromatography-mass spectrometry revealed that α-ClFA is elevated 5-fold in phorbol myristate-stimulated human monocytes rising to ≈20 μmol/L when compared with unstimulated cells. Using human THP-1 monocytes and RAW 264.7 cells as in vitro models, we tested the hypothesis that α-ClFA is a cell death mediator that could potentially participate in pathophysiological roles of monocytes in diseases, such as atherosclerosis. Indeed, 2-chlorohexadecanoic acid, the 16-carbon molecular species of α-ClFA, caused significant apoptosis of primary monocytes. Similarly, 2-chlorohexadecanoic acid also caused apoptosis in THP-1 human monocytes and RAW 264.7 mouse macrophages as determined by annexin V-propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining, respectively. 2-Chlorohexadecanoic acid treatment also increased caspase-3 activity and poly (ADP-ribose) polymerase cleavage in THP-1 cells. 2-Chlorohexadecanoic acid likely elicits apoptosis by increasing both reactive oxygen species production and endoplasmic reticulum stress because antioxidants and CCAAT/enhancer-binding protein homologous protein block such induced cell apoptosis.

CONCLUSIONS:

The stable chlorinated lipid, α-ClFA, accumulates in activated primary human monocytes and elicits monocyte apoptosis through increased reactive oxygen species production and endoplasmic reticulum stress, providing a new insight into chlorinated lipids and monocytes in inflammatory disease.

KEYWORDS:

apoptosis; macrophages; monocytes; peroxidase

PMID:
24371082
PMCID:
PMC3951512
DOI:
10.1161/ATVBAHA.113.302544
[Indexed for MEDLINE]
Free PMC Article
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