Content and activity of cAMP response element-binding protein regulate platelet-derived growth factor receptor-alpha content in vascular smooth muscles.
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-alpha receptor gene (PDGFRalpha). Adenovirus-mediated expression of constitutively active CREB mutants decreases PDGFRalpha mRNA, PDGFRalpha protein, and PDGFRalpha promoter-luciferase reporter activity in cultured SMCs. Expression of dominant negative CREB protein, A-CREB, increases PDGFRalpha protein content and the PDGFRalpha-promoter activity in SMCs. Active CREB prevents activation of PDGFRalpha promoter-luciferase reporter activity by CCAAT/enhancer-binding protein-delta (C/EBPdelta), shown to mediate IL-1beta stimulation of PDGFRalpha expression. Exposure of cultured SMCs to high glucose or reactive oxidant stress, which decrease CREB protein content and activity, increases PDGFRalpha protein content and promoter activity. Expression of active CREB blunts reactive oxidant stress-induced PDGFRalpha accumulation in SMCs. Loss of CREB protein in aortic walls of rats with streptozotocin-induced diabetes is accompanied by an increase in PDGFRalpha content. In Ob/Ob mice (which demonstrate reduced aortic wall CREB content vs. Ob/- controls), treatment with the peroxisomal proliferator-activated receptor gamma rosiglitazone increases CREB content and decreases PDGFRalpha content in the aortic wall. Thus, both in vitro and in vivo loss of CREB content and activity and subsequent accumulation of PDGFRalpha may contribute to SMC activation during diabetes.
Denver Research Institute, Denver Veterans Affairs Medical Center, University of Colorado Health Sciences Center, 1055 Clermont Street, Denver, CO 80220, USA.
Peter A
PA
Watson
Charles
C
Vinson
Albina
A
Nesterova
Jane E-B
JE
Reusch
D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D007333:Insulin Resistance; D009131:Muscle, Smooth, Vascular / Q000737:chemistry* / Q000166:cytology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha