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.

Our data provides a novel insight into an effect of telmisartan: telmisartan inhibits AT1R gene expression through PPARgamma activation. The dual inhibition of angiotensin II function by telmisartan - AT1R blockade and downregulation - would contribute to more complete inhibition of the renin-angiotensin system.

Abstract-Thyroid hormone has a broad effect on cardiovascular system. 3,3Ј,5-triiodo-L-thyronine (T3), a biologically active form of thyroid hormone, increases cardiac contractility. T3 causes arterial relaxation and reduction of systemic vascular resistance, resulting in an increase in cardiac output. However, the molecular mechanisms of vascular relaxation by T3 are incompletely characterized. We studied the effect of T3 on the angiotensin (Ang) II type 1 receptor (AT 1 R) expression in vascular smooth muscle cells. T3 dose-dependently decreased expression levels of AT 1 R mRNA, with a peak at 6 hours of stimulation. Binding assay using [ 125 I]Sar 1 -Ile 8 -Ang II revealed that AT 1 R number was decreased by stimulation with T3 without changing the affinity to Ang II. T3 reduced calcium response of vascular smooth muscle cells to Ang II by 26%. AT 1 R promoter activity measured by luciferase assay was reduced by 50% after 9 hours of T3 administration. mRNA stability was also decreased by T3. Real-time quantitative reverse transcriptionpolymerase chain reaction and Western blot analysis revealed that AT 1 R mRNA and protein were downregulated in the aorta of T3-treated rats. These results suggest that T3 downregulates AT 1 R expression both at transcriptional and posttranscriptional levels, and attenuates biological function of Ang II. Our results suggest that downregulation of AT 1 R gene expression may play an important role for T3-induced vascular relaxation. T hyroid hormone has various effects on the cardiovascular system. L-Thyroxine (T4), the major secretory product of the thyroid gland is inactive. Thyroxine 5Ј-deiodinase converts T4 to an active hormone, 3,3Ј,5-triiodo-L-thyronine (T3). 1 T3 binds to thyroid hormone receptor that belongs to the nuclear receptor family. The activated thyroid hormone receptor induces gene expression through binding to thyroid hormone response element (TRE) in the promoter region of target genes. 2 An increase in left ventricular contractility, tachycardia, and reduction of systemic vascular resistance induce high cardiac output state in hyperthyroidism. The positive inotropic and chronotropic action of T3 are direct effects of T3 on cardiac myocytes, and T3 activates many gene expressions such as myosin heavy chain and calcium transport/regulatory proteins in myocytes. [3][4][5] Reduction of systemic vascular resistance is also a direct effect of T3 on vascular smooth muscle cells (VSMCs). 6 -8 A recent report showed that T3 caused rapid relaxation of VSMCs, suggesting the presence of rapid nongenomic effect of T3. 9 It was also shown that T3-induced relaxation of VSMCs was not mediated by cAMP or NO. The target genes for T3 action in VSMCs, which are involved in vascular relaxation, have not been determined.Two isoforms for angiotensin (Ang) II receptor designated type 1 receptor (AT 1 R) 10 and type 2 receptor (AT 2 R) 11 are present. AT 1 R is a G protein-coupled receptor expressed in various tissues, including blood vessel, kidney, adrenal gland, liver, and reproduc...

Objective-Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions such as atherosclerosis and restenosis after angioplasty. Previous studies have demonstrated that tumor necrosis factor-␣ (TNF-␣) is a potent migration factor for VSMCs. cAMP-response element-binding protein (CREB) is the stimulusinduced transcription factor and activates transcription of target genes such as c-fos and interleukin-6. We examined whether CREB is involved in TNF-␣-induced VSMC migration. Methods and Results-TNF-␣ induced CREB phosphorylation with a peak at 15 minutes of stimulation. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNF-␣-induced CREB phosphorylation. Adenovirus-mediated overexpression of dominant-negative form of CREB suppressed TNF-␣-induced CREB phosphorylation and c-fos mRNA expression. VSMC migration was evaluated using a Boyden chamber. Overexpression of dominant-negative form of CREB suppressed VSMC migration as well as Rac1 expression induced by TNF-␣. Overexpression of dominant-negative Rac1 also inhibited TNF-␣-induced VSMC migration. Conclusion-Our