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Content and Activity of cAMP Response Element-Binding Protein Regulate Platelet-Derived Growth Factor Receptor- Content in Vascular Smooth Muscles

Denver Research Institute (P.A.W., J.E.-B.R.), Denver Veterans Affairs Medical Center and Department of Medicine (P.A.W., A.N., J.E.-B.R.), Division of Endocrinology, University of Colorado Health Sciences Center, Denver, Colorado 80220; and National Cancer Institute (C.V.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Jane E.-B. Reusch, M.D., Denver VA Medical Center, Room 9C-120, 1055 Clermont Street, Denver, Colorado 80220. E-mail: . jane.reusch{at}uchsc.edu

Experiments in vascular smooth muscle cells (SMCs) indicate that the transcription factor cAMP response element-binding protein (CREB), the cyclic nucleotide response element-binding protein, suppresses expression of the platelet-derived growth factor- receptor gene (PDGFR). Adenovirus-mediated expression of constitutively active CREB mutants decreases PDGFR mRNA, PDGFR protein, and PDGFR promoter-luciferase reporter activity in cultured SMCs. Expression of dominant negative CREB protein, A-CREB, increases PDGFR protein content and the PDGFR-promoter activity in SMCs. Active CREB prevents activation of PDGFR promoter-luciferase reporter activity by CCAAT/enhancer-binding protein- (C/EBP), shown to mediate IL-1ß stimulation of PDGFR expression. Exposure of cultured SMCs to high glucose or reactive oxidant stress, which decrease CREB protein content and activity, increases PDGFR protein content and promoter activity. Expression of active CREB blunts reactive oxidant stress-induced PDGFR accumulation in SMCs. Loss of CREB protein in aortic walls of rats with streptozotocin-induced diabetes is accompanied by an increase in PDGFR content. In Ob/Ob mice (which demonstrate reduced aortic wall CREB content vs. Ob/- controls), treatment with the peroxisomal proliferator-activated receptor rosiglitazone increases CREB content and decreases PDGFR content in the aortic wall. Thus, both in vitro and in vivo loss of CREB content and activity and subsequent accumulation of PDGFR may contribute to SMC activation during diabetes.

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