Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin.
Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeleton-related proteins were also detected. The results showed that Hcy (300-500 microM) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time- and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an alpha(5)beta(1)-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocyte-derived resistin, which provides further evidence of the adipose-vascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.
Jiang
Changtao
C
Dept. of Physiology and Pathophysiology, Peking Univ., Beijing, People's Republic of China.
Zhang
Heng
H
Zhang
Weizhen
W
Kong
Wei
W
Zhu
Yi
Y
Zhang
Hongquan
H
Xu
Qingbo
Q
Li
Yin
Y
Wang
Xian
X
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000096:biosynthesis*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D003598:Cytoskeletal Proteins; D039081:Integrin alpha5beta1; D052243:Resistin; D006710:Homocysteine; D051416:Focal Adhesion Protein-Tyrosine Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein