Published online before print November 15, 2004, doi: 10.1161/01.CIR.0000147825.97879.E7
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(Circulation. 2004;110:3335-3340.)
© 2004 American Heart Association, Inc.
Molecular Cardiology |
Resistin Promotes Smooth Muscle Cell Proliferation Through Activation of Extracellular Signal–Regulated Kinase 1/2 and Phosphatidylinositol 3-Kinase Pathways
From the Research Center for Cardiovascular Diseases at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston (P.C., E.T.H.Y.); Texas Heart Institute, St Luke’s Episcopal Hospital, Houston (P.C., J.T.W., E.T.H.Y.); Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station (I.S.); and Department of Cardiology, University of Texas M.D. Anderson Cancer Center, Houston (J.T.W., E.T.H.Y.).
Correspondence to Dr Edward T.H. Yeh, Department of Cardiology, Unit 449, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail etyeh{at}mdanderson.org
Received March 6, 2004; de novo received May 11, 2004; revision received June 21, 2004; accepted June 25, 2004.
Background— Resistin, a novel adipokine, is elevated in patients with type 2 diabetes and may play a role in the vascular complications of this disorder. One recent study has shown that resistin has a proinflammatory effect on endothelial cells. However, there is no information on whether resistin could also affect vascular smooth muscle cells (SMCs). Thus, the purpose of this study was to assess whether resistin could induce SMC proliferation and to study the mechanisms whereby resistin signals in SMCs.
Methods and Results— Human aortic smooth muscle cells (HASMCs) were stimulated with increasing concentrations of resistin for 48 hours. Cell proliferation was induced by resistin in a dose-dependent manner as assessed by direct cell counting. To gain more insights into the mechanism of action of resistin, we investigated the extracellular signal–regulated kinase (ERK) and/or phosphatidylinositol 3-kinase (PI3K) signaling pathways. Transient phosphorylation of the p42/44 mitogen-activated protein kinase (ERK 1/2) occurred after addition of resistin to HASMCs. U0126, a specific inhibitor of ERK phosphorylation, significantly inhibited ERK 1/2 phosphorylation and reduced resistin-simulated proliferation of HASMCs. LY294002, a specific PI3K inhibitor, also significantly inhibited HASMC proliferation after resistin stimulation.
Conclusions— Our results demonstrate that resistin induces HASMC proliferation through both ERK 1/2 and Akt signaling pathways. The proliferative action exerted by resistin on HASMCs may account in part for the increased incidence of restenosis in diabetes patients.
Key Words: diabetes mellitus • obesity • angioplasty • restenosis
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