Basic fibroblast growth factor decreases elastin gene transcription in aortic smooth muscle cells.
The extracellular matrix (ECM) protein elastin plays an essential role in the cardiovascular system by imparting elasticity to blood vessel wall. In this study, we examined the effect of basic fibroblast growth factor (bFGF) on the expression of elastin in aortic smooth muscle cells (SMC) to gain insight into events associated with cardiovascular diseases. The results show that bFGF treatment of SMC causes a significant decrease in elastin mRNA and secreted tropoelastin levels. Nuclear run-on analyses demonstrate that the downregulation is due to a decrease in the level of elastin gene transcription. Transient transfections of SMC with wild-type and mutated elastin gene promoter/chloramphenicol acetyl transferase (CAT) constructs show that a previously identified activator protein-1-cAMP response element (AP1/CRE) (-564 to -558-bp) within the elastin promoter mediates the bFGF-dependent downregulation of elastin gene transcription in SMC. Addition of bFGF to SMC activates the extracellular signal-regulated kinases 1/2 (ERK1/2) resulting in their translocation into the nucleus and subsequent induction of Fra-1. The addition of PD-98059, an inhibitor of ERK1/2 kinase, abrogates the bFGF-dependent decrease of elastin mRNA in SMC. The described inhibitory effect of bFGF on elastin gene expression in SMC may significantly contribute to the inefficient repair of elastin in early stages of vascular wall injury.
Carreras
Isabel
I
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Rich
Celeste B
CB
Panchenko
Mikhail P
MP
Foster
Judith Ann
JA
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004549:Elastin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000099169:Fos-Related Antigen 1
D000242:Cyclic AMP; D004549:Elastin; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D005419:Flavonoids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one