GATA-6 regulates genes promoting synthetic functions in vascular smooth muscle cells.
OBJECTIVE
Previous studies suggested the zinc-finger transcription factor GATA-6 inhibits vascular smooth muscle cell (VSMC) proliferation and promotes the contractile VSMC phenotype. The objective of this study was to identify bona fide target genes regulated by GATA-6 in VSMCs.


RESULTS
Microarray analyses were performed comparing mRNA from rat aortic smooth muscle cells (SMCs) infected with either adenovirus encoding a dominant-negative GATA-6/engrailed fusion protein or with control adenovirus. These studies identified 122 genes differentially expressed by at least 2-fold, including multiple genes involved in cell-cell signaling and cell-matrix interactions. Among these, endothelin-1 and the angiotensin type(1a) (AT(1a)) receptor are known to be induced in VSMCs in response to inflammatory stimuli and to be expressed in a GATA-dependent manner in cardiac myocytes in response to hemodynamic stress. Consistent with these findings, the endothelin-1 and AT(1a) receptor promoters were activated by forced expression of GATA-6 and repressed by forced expression of GATA-6/engrailed. Surprisingly, genes encoding SMC contractile proteins were not altered, and myocardin-induced SMC differentiation was not impaired in GATA-6(-/-) embryonic stem cells.


CONCLUSIONS
These data demonstrate that in VSMCs, GATA-6 regulates a set of genes associated with synthetic SMC functions and suggest that this transcriptional pathway may be independent from myocardin-induced SMC differentiation. An unbiased microarray screen of genes regulated by GATA-6 in VSMCs identified multiple genes involved in cell-cell signaling and cell-matrix interactions. The endothelin-1 and the AT1a receptor genes were shown to be direct GATA-6 target genes. These data suggest that GATA-6 plays a role in promoting synthetic functions in VSMCs.
Lepore
John J
JJ
Molecular Cardiology Research Center, Department of Medicine, University of Pennsylvania Health System, Philadelphia 19104, USA. john.lepore@uphs.upenn.edu <john.lepore@uphs.upenn.edu>
Cappola
Thomas P
TP
Mericko
Patricia A
PA
Morrisey
Edward E
EE
Parmacek
Michael S
MS
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D050993:GATA6 Transcription Factor; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D041681:NIH 3T3 Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D000099251:Myocardin
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D019332:Endothelin-1; D050993:GATA6 Transcription Factor; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C063459:En protein, Drosophila; C494759:GATA6 protein, human; C494760:Gata6 protein, mouse