on December 9, 2004
Published online before print December 9, 2004, doi: 10.1161/01.ATV.0000152725.76020.3c
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Submitted on August 20, 2004
Accepted on November 29, 2004
GATA-6 Regulates Genes Promoting Synthetic Functions in Vascular Smooth Muscle Cells
John J. Lepore *;
From the Molecular Cardiology Research Center, Department of Medicine, University of Pennsylvania Health System, Philadelphia.
* To whom correspondence should be addressed. E-mail: john.lepore{at}uphs.upenn.edu.
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.
Methods and 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 type1a (AT1a) 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 AT1a 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-/- ES 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.
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