The Antiatherogenic Effect of Fish Oil in Male Mice Is Associated with a Diminished Release of Endothelial ADAM17 and ADAM10 Substrates.

Abstract

BACKGROUND:

Growing evidence suggests that disintegrin and metalloprotease (ADAM) 17 (ADAM17) and ADAM10 contribute to the pathogenesis of vascular diseases. ADAM17 promotes inflammatory processes by liberating tumor necrosis factor α, interleukin 6 receptor (IL-6R), and tumor necrosis factor receptor 1 (TNFR1). ADAM17 and ADAM10 modulate vascular permeability by cleaving endothelial adhesion molecules such as junctional adhesion molecule A (JAM-A) and vascular endothelial cadherin (VE-cadherin), respectively.

OBJECTIVE:

This study was designed to investigate whether a link might exist between the protective effects of fish oil (FO) supplementation against atherosclerosis and ADAM function.

METHODS:

Male LDL receptor knockout (LDLR(-/-)) mice and male wild-type (WT) mice were fed a Western diet (200 g/kg fat, 1.5 g/kg cholesterol) containing either 20% lard (LDLR(-/-)-lard and WT-lard groups) or 10% lard combined with 10% FO (LDLR(-/-)-FO and WT-FO groups) for 12 wk. Atherosclerotic lesion development and fatty acid composition of liver microsomes were evaluated. ADAM10 and ADAM17 expression was determined by quantitative real-time polymerase chain reaction and immunoblot analyses. Concentrations of soluble ADAM substrates in plasma and liver extracts were measured by ELISA.

RESULTS:

Diets supplemented with FO markedly reduced development of early atherosclerotic lesions in LDLR(-/-) mice (LDLR(-/-)-lard group vs. LDLR(-/-)-FO group mean ± SD: 29.6 ± 6.1% vs. 22.5 ± 4.2%, P < 0.05). This was not accompanied by changes in expression of ADAM17 or ADAM10 in the aorta or liver. No dietary effects on circulating TNFR1 (LDLR(-/-)-lard group vs. LDLR(-/-)-FO group mean ± SD: 1.22 ± 0.23 vs. 1.39 ± 0.28, P > 0.2) or IL-6R (1.06 ± 0.12 vs. 0.98 ± 0.09 fold of WT-lard group, P > 0.1), classical substrates of ADAM17 on macrophages, and neutrophil granulocytes were observed. However, a reduction in atherosclerotic lesions in the LDLR(-/-)-FO group was accompanied by a significant reduction in the circulating endothelial cell adhesion molecules JAM-A (LDLR(-/-)-lard group vs. LDLR(-/-)-FO group mean ± SD: 1.42 ± 0.20 vs. 0.95 ± 0.56 fold of WT-lard group, P < 0.05), intercellular adhesion molecule 1 (1.15 ± 0.14 vs. 0.88 ± 0.17 fold of WT-lard group, P < 0.05), and VE-cadherin (0.88 ± 0.12 vs. 0.72 ± 0.15 fold of WT-lard group, P < 0.05), reflecting reduced ADAM activity in endothelial cells.

CONCLUSION:

FO exerted an antiatherogenic effect on male LDLR(-/-) mice that was accompanied by a reduced release of ADAM17 and ADAM10 substrates from endothelial cells. It is suggested that FO-decreased ADAM activity contributes to improved endothelial barrier function and thus counteracts intimal lipoprotein insudation and macrophage accumulation.

• Authors: Nancy Speck, Corinna Brandsch, Nadine Schmidt, Narges Yazdekhasti, Frank Hirche, Ralph Lucius, Gerald Rimbach, Gabriele I Stangl, Karina Reiss
• Journal: The Journal of nutrition (J Nutr) Vol. 145 Issue 6 Pg. 1218-26 (Jun 2015) ISSN: 1541-6100 [Electronic] United States
• PMID: 25926412 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Society for Nutrition.

Chemical References

• Cholesterol, Dietary
• Dietary Fats
• Fish Oils
• Membrane Proteins
• RNA, Messenger
• Receptors, LDL
• Intercellular Adhesion Molecule-1
• Amyloid Precursor Protein Secretases
• ADAM Proteins
• ADAM10 Protein
• Adam10 protein, mouse
• ADAM17 Protein
• ADAM17 protein, human
• Adam17 protein, mouse
• lard

Topics

• ADAM Proteins (genetics, metabolism)
• ADAM10 Protein
• ADAM17 Protein
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Animals
• Aorta (drug effects, metabolism)
• Atherosclerosis (drug therapy, prevention & control)
• Cholesterol, Dietary (administration & dosage, adverse effects)
• Diet, Western (adverse effects)
• Dietary Fats (administration & dosage)
• Dietary Supplements
• Endothelial Cells (drug effects, metabolism)
• Endothelium, Vascular (drug effects, metabolism)
• Fish Oils (pharmacology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Liver (drug effects, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• RNA, Messenger (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Receptors, LDL (genetics, metabolism)