Apelin is an
adipokine that has a critical role in the development of
atherosclerosis, which may offer potential for
therapy. Because migration of vascular smooth muscle cells (VSMCs) is a key event in the development of
atherosclerosis, understanding its effect on the atherosclerotic vasculature is needed. Here we investigated the effect of
apelin on VSMC migration and the possible signaling mechanism. In cultured rat VSMCs,
apelin dose- and time-dependently promoted VSMC migration.
Apelin increased the phosphorylation of Akt, whereas
LY294002, an inhibitor of
phosphatidylinositol 3-kinase (PI3K), and an Akt1/2
kinase inhibitor blocked the
apelin-induced VSMC migration.
Apelin dose-dependently induced phosphorylation of Forkhead box O3a (FoxO3a) and promoted its translocation from the nucleus to cytoplasm, which were blocked by
LY294002 and Akt1/2
kinase inhibitor. Furthermore,
apelin increased
matrix metalloproteinase 2 (MMP-2) expression and gelatinolytic activity. Overexpression of a constitutively active, phosphorylation-resistant mutant, TM-FoxO3a, in VSMCs abrogated the effect of
apelin on MMP-2 expression and VSMC migration. ARP101, an inhibitor of MMP-2, suppressed
apelin-induced VSMC migration. Moreover, the levels of
apelin, phosphorylated Akt, FoxO3a, and MMP-2 were higher in human carotid-artery
atherosclerotic plaque than in adjacent normal vessels. We demonstrate that PI3K/Akt/FoxO3a signaling may be involved in
apelin inducing VSMC migration. Phosphorylation of FoxO3a plays a central role in mediating the
apelin-induced MMP-2 activation and VSMC migration.