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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1549.)
© 2007 American Heart Association, Inc.

Vascular Biology

Inducible cAMP Early Repressor Inhibits Growth of Vascular Smooth Muscle Cell

Hideki Ohtsubo; Toshihiro Ichiki; Ryohei Miyazaki; Keita Inanaga; Ikuyo Imayama; Yasuko Hashiguchi; Junichi Sadoshima; Kenji Sunagawa

From the Department of Cardiovascular Medicine (H.O., T.I., R.M., K.I., I.I., Y.H., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and the Cardiovascular Research Institute (J.S.), University of Medicine and Dentistry of New Jersey.

Correspondence to Toshihiro Ichiki, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashiku, 812-8582 Fukuoka, Japan. E-mail ichiki{at}cardiol.med.kyushu-u.ac.jp

Objective— The role of inducible cAMP early repressor (ICER), a transcriptional repressor, in the vascular remodeling process has not been determined. We examined whether ICER affects growth of vascular smooth muscle cells (VSMCs).

Methods and Results— Semi-quantitative RT-PCR and Western blot analysis showed that expression of ICER was increased in beraprost (a prostaglandin I₂ analogue)-stimulated VSMCs in a time- and dose-dependent manner. The induction of ICER was inhibited by pretreatment with H89, a protein kinase A (PKA) inhibitor, suggesting that PKA mediates the induction of ICER expression. Beraprost suppressed platelet-derived growth factor–induced thymidine incorporation in VSMCs, which was reversed by transfection of short interfering RNA for ICER, not by scramble RNA. Overexpression of ICER by an adenovirus vector attenuated neointimal formation (intima/media ratio) by 50% compared with overexpression of LacZ. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling–positive cells was increased and the number of Ki-67–positive cells was decreased in ICER-transduced artery.

Conclusion— These results suggest that ICER induces apoptosis and inhibits proliferation of VSMCs, and plays a critical role in beraprost-mediated suppression of VSMC proliferation. ICER may be an important endogenous inhibitor of vascular proliferation.

Inducible cAMP early repressor (ICER) is involved in beraprost-induced growth inhibition of vascular smooth muscle cells. Overexpression of ICER suppressed neointimal formation in balloon-injured artery, suggesting that ICER may be an important negative regulator of the vascular remodeling process and an effective therapeutic tool to treat vascular proliferative disease.

Key Words: PGI₂ analogue • inducible cAMP early repressor • neointimal formation • VSMC

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