© 1999 American Heart Association, Inc.
Original Contribution |
Reversal of GATA-6 Downregulation Promotes Smooth Muscle Differentiation and Inhibits Intimal Hyperplasia in Balloon-Injured Rat Carotid Artery
From the Division of Cardiovascular Research (T.M., Z.L., K.W.), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass; the Department of Medicine, Division of Cardiology (S.L.M.), and the Department of Developmental and Molecular Biology (S.L.M., T.E.), Albert Einstein College of Medicine, Bronx, NY.
Correspondence to Kenneth Walsh, PhD, Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, Boston, MA 02135. E-mail kwalsh{at}opal.tufts.edu
Abstract—The
GATA-6 transcription factor is expressed in quiescent
vascular smooth muscle cells (VSMCs) in culture, and levels of its
transcript are rapidly downregulated on mitogen stimulation. In this
study, we demonstrate that the GATA-6 transcript,
protein, and DNA-binding activity are downregulated in rat carotid
arteries on balloon injury. Downregulation was detected at 1 and 3 days
after injury and recovered by 7 days. To assess the role of GATA-6
downregulation in injury-induced vascular lesion formation, adenoviral
vectors were used to express wild-type human GATA-6 cDNA
(Ad-GATA6) or an inactive mutant cDNA that lacks a portion of the
zinc-finger domain (Ad-GATA6
ZF). Adenovirus-mediated
GATA-6 gene transfer to the vessel wall after balloon
injury partially restored the levels of GATA-6 protein and DNA-binding
activity to before injury levels. The local delivery of Ad-GATA6 but
not Ad-GATA6ZF inhibited lesion formation by 46% relative to saline
control and 50% relative to a control adenovirus that expressed
lacZ. Local delivery of Ad-GATA6 also reversed changes
in the expression patterns of smooth muscle myosin heavy chain, smooth
muscle 
-actin, calponin, vinculin, metavinculin, and proliferating
cell nuclear antigen that are associated with injury-induced VSMC
phenotypic modulation. These data indicate that the injury-induced
downregulation of GATA-6 is an essential feature of VSMC phenotypic
modulation that contributes to vessel lesion formation.
Key Words: gene expression • adenovirus • restenosis • muscle, smooth • genes
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