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


CONCLUSIONS
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.
Department of Dermatology.
Nancy
N
Speck
Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Corinna
C
Brandsch
Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Nadine
N
Schmidt
Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Narges
N
Yazdekhasti
Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Frank
F
Hirche
Institute of Anatomy, and.
Ralph
R
Lucius
Institute of Human Nutrition and Food Science, Christian-Albrechts University of Kiel, Kiel, Germany; and.
Gerald
G
Rimbach
Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Gabriele I
GI
Stangl
Department of Dermatology, kreiss@dermatology.uni-kiel.de.
Karina
K
Reiss
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000517:prevention & control*; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D066273:Diet, Western / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage; D019587:Dietary Supplements; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005395:Fish Oils / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D002791:Cholesterol, Dietary; D004041:Dietary Fats; D005395:Fish Oils; D008565:Membrane Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D018799:Intercellular Adhesion Molecule-1; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C029310:lard
ADAM; LDLR knockout; atherosclerosis; endothelial permeability; fish oil; shedding