Endothelin-1- and depolarization-induced differential regulation of cAMP response element-binding protein in proliferating and developed vascular smooth muscle.
Regulation of the transcription factor cAMP response element-binding protein (CREB) is important for gene expression in vascular smooth muscle (VSM). This study has examined the intracellular regulation of CREB by endothelin-1 (ET-1) and depolarization in native VSM, comparing proliferative and fully differentiated phenotypes. Portal veins from neonatal (proliferative) and 6-week-old (differentiated) rats were stimulated with ET-1 or K(+). In both phenotypes, CREB activation was increased by ET-1 although the time course was prolonged in neonatal VSM. This paralleled a prolonged ET-1-induced [Ca(2+)](i) increase. ET-1-induced CREB activation was dependent on extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibited by BAPTA but not by a calmodulin-dependent protein kinase (CamK) inhibitor. In contrast, CREB activation induced by depolarization in both neonatal and developed VSM was significantly reduced by CaMK inhibition and by ERK1/2 inhibition. Therefore, CREB activation is regulated differentially in VSM depending upon stimulus; however, this is not altered in different growth states.
Egan
Colin G
CG
School of Medical Sciences, College of Life Sciences and Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Nixon
Graeme F
GF
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D015151:Immunoblotting; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D013997:Time Factors
D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D019332:Endothelin-1; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium