Abstract 9079: Omentin Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E Knockout Mice

Abstract

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease worldwide. Obesity is associated with an increased risk of AAA. Omentin is an adipokine, which is downregulated by obesity. Here we investigated the effect of omentin on angiotensin (Ang) II-induced AAA formation in apolipoprotein-E knockout (apoE-KO) mice. Methods and Results: ApoE-KO mice were crossed with transgenic mice expressing the human omentin in fat tissue (OMT-Tg mice). ApoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion. ApoE-KO/OMT-Tg mice exhibited a reduced maximal diameter of AAA compared with apo-E KO mice evaluated by macroscopic and ultrasound analyses. ApoE-KO/OMT-Tg mice showed a reduction of elastic fiber degradation in aorta compared with apoE-KO mice. ApoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, pro-inflammatory mediators and macrophage surface marker, F4/80, in aortic walls compared with apo-E-KO mice. Conversely, intravenous administration of adenoviral vectors expressing omentin (Ad-OMT) significantly reduced maximal diameter and elastic fiber degradation of abdominal aorta after Ang II infusion in apoE-KO mice compared with control Ad-β-gal treatment. Treatment of human monocyte-derived macrophages with omentin protein attenuated activity and expression of MMP9 and NF-κB phosphorylation after stimulation with lipopolysaccharide. Treatment of human aortic smooth muscle cells with omentin protein attenuated activity and expression of MMP2 after stimulation with tumor necrosis factor α. The suppressive effects of omentin on MMP9 and MMP2 expression in macrophages and vascular smooth muscle cells were reversed by inhibition of PI3-kinase/Akt signaling or blockade of integrin αVβ3. Finally, continuous administration of PI3-kinase inhibitor LY294002 reversed the suppressive effects of Ad-OMT on maximal diameter and elastic fiber degradation of abdominal aorta in apoE-KO mice after Ang II infusion. Conclusion: Our data indicate that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA by reducing MMP9 and MMP2 expression through the integrin αVβ3/PI3-kinase/Akt signaling in the vascular wall.