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 a, 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 ADAM 17 or ADAM 10 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 ADAM 10 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.