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 alpha-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.
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 alpha-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.
Authors: Nazira Ozgen; Jianfen Guo; Zoya Gertsberg; Peter Danilo; Michael R Rosen; Susan F Steinberg Journal: Mol Pharmacol Date: 2009-07-20 Impact factor: 4.436