Apelin induces vascular smooth muscle cells migration via a PI3K/Akt/FoxO3a/MMP-2 pathway.
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.
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Cheng
C
Wang
Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
Jianyan
J
Wen
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Yun
Y
Zhou
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Li
L
Li
Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing 100191, China.
Xiaobing
X
Cui
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Jinyu
J
Wang
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, 100029, China.
Lin
L
Pan
Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
Zhidong
Z
Ye
Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: liupeng5417@163.com.
Peng
P
Liu
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China. Electronic address: pathophy@bjmu.edu.cn.
Liling
L
Wu
D000818:Animals; D000073861:Apelin; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D004790:Enzyme Induction; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D000073861:Apelin; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C498579:Apln protein, rat; C499515:FOXO3 protein, rat; C522363:Mmp2 protein, rat
Apelin; Atherosclerosis; FoxO3a; MMP-2; Vascular smooth muscle cells