Published online before print August 25, 2003, doi: 10.1161/01.CIR.0000085164.13439.89
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(Circulation. 2003;108:1246.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Apoptosis Induced by Inhibition of Cyclic AMP Response Element–Binding Protein in Vascular Smooth Muscle Cells
From the Departments of Cardiovascular Medicine (T.T., T. Ichiki, K.F., H.O., N.I., S.M., H.S., K.E., A.T.) and Cancer Therapy and Research (T.M.), Kyushu University Graduate School of Medical Sciences, and the Cardiovascular Research Institute and Internal Medicine III (R.S., H.K., T. Imaizumi), Kurume University School of Medicine, Fukuoka, Japan.
Correspondence to Toshihiro Ichiki, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan (e-mail ichiki{at}cardiol.med.kyushu-u.ac.jp). Reprint requests can be also forwarded to Hisashi Kai, MD, Cardiovascular Research Institute, Kurume University, 67 Asahimachi, Kurume, 830-0011 Fukuoka, Japan.
Received December 3, 2002; revision received May 5, 2003; accepted May 9, 2003.
Background— The balance between apoptosis and proliferation of vascular smooth muscle cells (VSMCs) is believed to contribute to the vascular remodeling process. Cyclic AMP response element–binding protein (CREB) is a critical transcription factor for the survival of neuronal cells and T lymphocytes. However, the role of CREB in blood vessels is incompletely characterized.
Methods and Results— Nuclear staining with Hoechst 33258 or propidium iodine showed an increase in apoptotic cells with activation of caspase-3 in VSMCs infected with adenovirus expressing the dominant-negative form of CREB (AdCREBM1). Basal expression of Bcl-2 and Bcl-2 promoter activity were decreased by infection with AdCREBM1. Immunohistochemistry revealed that CREB was mainly induced and activated in the neointimal 
-smooth muscle actin–positive cells of rat carotid artery after balloon injury. Infection with AdCREBM1 suppressed neointimal formation (intima-media ratio) by 33.8% after 14 days of injury, which was accompanied by an increase in apoptosis as indicated by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling–positive cells and a decrease in bromodeoxyuridine incorporation.
Conclusions— These results suggest that CRE-dependent gene transcription might play an important role in the survival and proliferation of VSMCs. CREB might be a novel transcription factor mediating the vascular remodeling process and a potential therapeutic target for atherosclerotic disease.
Key Words: apoptosis • muscle, smooth • vasculature • phosphates • balloon
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