An adipokine omentin prevents pathological vascular remodeling

Abstract

Background: Obese states are associated with the development of atherosclerosis and vascular restenosis after angioplasty. Omentin is an adipocytokine whose concentrations are reduced in obese individuals. Recently, we have reported that circulating omentin levels are down-regulated in association with obesity-linked disorders including carotid atherosclerosis and coronary artery disease. Here, we investigated the role of omentin on neointimal hyperplasia and Vascular Smooth Muscle Cell (VSMC) behavior in vivo and in vitro. Methods and results: An adenoviral vector expressing human Omentin (Ad-OMT) or β-galactosidase as a control was injected into the jugular vein of Wild-Type (WT) mice 3 d prior to vascular injury. Left femoral arteries of mice were injured by a stainless-steel wire inserted from the lumen. Although human omentin protein could not be detected in plasma in control WT mice, plasma human omentin levels were increased to 1353.9±169.6 ng/ml in Ad-OMT-treated WT mice on the 5th day after injection. At 21 days after vascular injury, systemic delivery of Ad-OMT significantly attenuated neointimal thickening compared with control (p<0.01, n=8). Ad-OMT decreased the number of bromodeoxyuridine (BrdU) positive proliferating cells in the neointima at day 7 after vascular injury (p<0.01, n=5). In cultured VSMCs, treatment with recombinant omentin protein attenuated DNA synthesis and chemotactic activity induced by various growth factors as assessed by BrdU incorporation and Boyden chamber assays, respectively. Treatment with omentin suppressed growth factor-induced phosphorylation of ERK in VSMCs. Treatment of VSMCs with omentin stimulated the phosphorylation of AMPK in a time-dependent manner. Furthermore, transduction with dominant-negative AMPK prevented the inhibitory effect of omentin on growth factor-stimulated VSMC proliferation and ERK phosphorylation. Conclusion: Omentin attenuates neointimal hyperplasia after vascular injury and suppresses VSMC growth through its ability to activate AMPK, suggesting that omentin can represent a novel target molecule for the prevention of pathological remodeling.