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(Circulation Research. 2006;98:913.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Novel Role for STAT-5B in the Regulation of Hsp27–FGF-2 Axis Facilitating Thrombin-Induced Vascular Smooth Muscle Cell Growth and Motility

Huiqing Cao, Nagadhara Dronadula, Farhan Rizvi, Quanyi Li, Kalyan Srivastava, William T. Gerthoffer, Gadiparthi N. Rao

From the Department of Physiology (H.C., N.D., F.R., Q.L., K.S., G.N.R.), University of Tennessee Health Science Center, Memphis; and Department of Pharmacology (W.T.G.), University of Nevada School of Medicine, Reno.

Correspondence to Gadiparthi N. Rao, PhD, Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Memphis, TN 38163. E-mail grao{at}physio1.utmem.edu

Previously, we have demonstrated that STAT-3 plays a role in thrombin-induced VSMC motility. To learn more about the role of STATs in the mitogenic and chemotactic signaling events of thrombin, here we have studied the role of STAT-5. Thrombin activated STAT-5 as measured by its tyrosine phosphorylation, DNA binding, and reporter gene activity. Inhibition of STAT-5B, but not STAT-5A, by adenovirus-mediated expression of its respective dominant-negative mutants suppressed thrombin-induced VSMC growth and motility. Thrombin induced the expression of Hsp27 and FGF-2 in a time- and STAT-5B-dependent manner in VSMC. In addition, small interfering RNA-directed depletion of Hsp27 levels or adenovirus-mediated expression of its dominant-negative mutant attenuated thrombin-induced FGF-2 expression, growth, and motility of VSMC. An increased association of STAT-5B with STAT-3 occurred in response to thrombin and adenovirus-mediated expression of dnSTAT-3 suppressed thrombin-induced Hsp27 and FGF-2 induction, DNA synthesis and motility in VSMC. Together, these results indicate that thrombin-induced VSMC growth and motility require STAT-5B/STAT-3–dependent expression of Hsp27 and FGF-2. These observations also suggest that STAT-5B/STAT-3/Hsp27/FGF-2 signaling via its involvement in the regulation of VSMC growth and motility may play an important role in the pathogenesis of vascular diseases such as restenosis after angioplasty.

Key Words: fibroblast growth factor-2 • heat shock protein 27 • G protein-coupled receptor • signal transducer and activator of transcription • vascular smooth muscle cell

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