Published online before print May 10, 2001, doi: 10.1161/hh1001.090840
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© 2001 American Heart Association, Inc.
Cellular Biology |
Thrombin Regulates Insulin-Like Growth Factor-1 Receptor Transcription in Vascular Smooth Muscle
Characterization of the Signaling Pathway
From the Division of Nephrology (J.D.) and Department of Pathology (T.P.), Emory University, Atlanta, Ga; the Division of Cardiology (M.B., B.M.), University Hospital of Geneva, Geneva, Switzerland; and the Division of Cardiovascular Diseases (P.D.), University of Kansas, Kansas City, Kans.
Correspondence to Patrick Delafontaine, MD, Division of Cardiovascular Diseases, 1001 Eaton Building, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160. E-mail pdelafontaine{at}kumc.edu
Abstract—We have previously demonstrated that thrombin upregulation of insulin-like growth factor-1 receptor (IGF-1R) is essential for thrombin-induced mitogenic signaling. To characterize the mechanisms involved, we studied transcription of the IGF-1R gene in rat aortic smooth muscle cells. Thrombin markedly increased IGF-1R mRNA levels, peaking at 3 hours (112±7% above control). This effect was mimicked by the hexapeptide SFFLRN (that functions as a tethered ligand) and was blocked by the thrombin inhibitor hirudin. Nuclear run-on assays indicated that thrombin stimulated IGF-1R gene transcription by 2.1-fold, and this was confirmed with the use of actinomycin D. Thrombin-mediated upregulation of IGF-1R mRNA and protein levels was protein kinase C independent but was completely inhibited by the protein tyrosine kinase inhibitor genistein and by the antioxidants N-acetyl-L-cysteine and pyrrolidinedithiocarbamate, suggesting the involvement of reactive oxygen species. The thrombin-induced increase in IGF-1R mRNA was inhibitable by diphenyleneiodonium chloride but not by other inhibitors of cellular oxidase systems, suggesting that NAD(P)H oxidase was necessary for the increase. Furthermore, inhibitors of the epidermal growth factor receptor kinase, Janus kinase-2 kinase, and Src kinase did not block the effect. Thus, thrombin transcriptionally regulates the IGF-1R gene via a redox-sensitive protein tyrosine kinase–dependent pathway that does not require protein kinase C activation. In view of our prior data indicating that IGF-1R density is a critical determinant of vascular smooth muscle cell growth, our findings have particular relevance to understanding mechanisms whereby growth factors such as thrombin regulate vascular proliferation in vivo.
Key Words: growth factors • signal transduction • gene regulation
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