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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:309.)
© 2005 American Heart Association, Inc.

Vascular Biology

GATA-6 Regulates Genes Promoting Synthetic Functions in Vascular Smooth Muscle Cells

John J. Lepore; Thomas P. Cappola; Patricia A. Mericko; Edward E. Morrisey; Michael S. Parmacek

From the Molecular Cardiology Research Center, Department of Medicine, University of Pennsylvania Health System, Philadelphia.

Correspondence to John J. Lepore, MD, Molecular Cardiology Research Center, University of Pennsylvania, 951 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. 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 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 AT_1a 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.

Key Words: gene regulation • smooth muscle differentiation • vascular biology • GATA-6

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