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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:404.)
© 2003 American Heart Association, Inc.

Vascular Biology

GATA-6 Is Involved in PPAR-Mediated Activation of Differentiated Phenotype in Human Vascular Smooth Muscle Cells

Mitsuru Abe; Koji Hasegawa; Hiromichi Wada; Tatsuya Morimoto; Tetsuhiko Yanazume; Teruhisa Kawamura; Maretoshi Hirai; Yutaka Furukawa; Toru Kita

From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Koji Hasegawa, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp

Objective— Peroxisome proliferator-activated receptor- (PPAR) is a member of the nuclear receptor superfamily involved in the growth and differentiation of many cell types. Although the activation of PPAR in human vascular smooth muscle cells (VSMCs) inhibits the growth of these cells, the precise mechanism of this effect is unknown. PPAR-mediated growth inhibition of VSMCs is associated with the induction of the differentiated phenotype. A zinc finger transcription factor, GATA-6, has been implicated in the maintenance of the differentiated phenotype in VSMCs.

Methods and Results— The administration of 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂), a naturally occurring PPAR ligand, and troglitazone, a thiazolidinedione derivative, induced the expression of smooth muscle myosin heavy chain and smooth muscle -actin, highly specific markers for differentiated VSMCs. Stimulation of proliferative VSMCs with PPAR ligands also increased the activity of the transfected wild-type smooth muscle myosin heavy chain promoter but not that of the mutant promoter, in which a GATA-6 binding site was mutated. Compatible with the role of GATA-6, both 15d-PGJ₂ and troglitazone upregulated the DNA binding activity of GATA-6 in proliferative VSMCs.

Conclusions— The activation of PPAR-dependent pathways induces the differentiated phenotype in proliferative VSMCs, and this induction is mediated, in part, through a GATA-6–dependent transcriptional mechanism.

Key Words: peroxisome proliferator-activated receptor-&ggr • GATA-6 • vascular smooth muscle cells • phenotypic modulation

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