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.
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...
Abstract-The distribution of apolipoprotein (apo) J during the development of atherosclerosis in the human aorta was evaluated by immununohistochemical observation, together with the other apolipoprotein A-I, A-II, B, C-III, and E. Although apoJ was never observed in the normal aorta (ie, without any intimal lesions or intimal thickening), it was distributed not only in the intima but also in the media of aortas with diffuse, intimal thickening or atherosclerotic lesions. Double immunostaining with antibodies for apoJ and ␣-smooth muscle actin revealed apoJ deposition in smooth muscle cells (SMCs) or the aortic stroma in the vicinity of SMCs. The extent of apoJ distribution in the aortic wall increased with the degree of atherosclerosis development. In addition, the distribution pattern of apoJ was very similar to that of apoA-I and E. In situ hybridization with human apoJ cDNA demonstrated intense signals in cells scattered within the subendothelial space and medial SMCs of the aorta with advanced atherosclerosis but not in those of the normal aorta without intimal thickening. Furthermore, reverse transcriptase-polymerase chain reaction of the cultured human aortic SMCs revealed apoJ mRNA expression in these cells. The results indicate that apoJ in the aortic wall originates from not only apoJ circulated in the plasma but also apoJ produced by SMCs in the aortic wall. Considering the similarities of the distribution between apoJ and apo-A-I or E, we hypothesize that apoJ possibly has a protective role against human atherosclerosis by its involvement with cholesterol transport from the aortic wall to the liver.
Activated phosphoinositide 3-kinase (PI3K) and its downstream target Akt are essential for the ®broblast transformation induced by many viral products. Tax, encoded by human T-cell leukemia virus type I (HTLV-I), has been demonstrated to induce the transformation of rat ®broblast Rat-1 cell through NF-kB activation. By stable transfection of Rat-1 cells with expressing constructs of Tax and its mutant M47, which is defective in HTLV-I LTR transactivation, we selected their transformed clones, which have characteristics of NFkB activation and colony formation beyond the cell monolayer (a malignant phenotype). However, these two characteristics in the transformed clones of Tax and M47 disappear after these cells have been treated with wortmannin, a speci®c inhibitor of PI3K. Further, increased activity of the PI3K/Akt is observed in the transformed clones of Tax and M47 as compared to the clones of empty vector Neo and the M148, which is defective in NF-kB activation and cell transformation. Increased activity of PI5K is present in the transformed clones of both Tax and M47 and in the M148 clone as compared to that in the Neo cell. It is known that the eciency of Tax-induced cell transformation is not high; a minority of Tax-expressing clones show transformation, although the majority of Tax-expressing clones show activated NF-kB. A Tax-expressing, nontransformed clone after transfection with an active form of the catalytic subunit of PI3K, p110a, becomes transformed. Consistent with these results, a Tax highlyexpressing human T-cell line MT2 exhibits both higher polyphosphoinositide turnover and higher activities of PI3K and PI5K than those of Jurkat or MT1 and HTLV-I-negative and a Tax-unexpressing cell line, respectively. These results demonstrate that the activation of the PI3K/Akt signaling pathway, excepting for the NF-kB, is also required for the cell transformation induced by Tax. Oncogene (2001) 20, 2514 ± 2526.
The evolution of atherosclerotic lesions is suppressed in the intima of the human coronary artery, beneath myocardial bridges. To elucidate the mechanism of the protective effect, we investigated morphological changes using the rabbit coronary artery as a model. Rabbit fed a 1%-cholesterol diet were killed at intervals up to 20 weeks. Two short segments of the left coronary arteries running in the epicardial adipose tissue (EpiLAD) and subsequently running in the myocardium (MyoLAD) were compared morphologically. The intima of the EpiLAD had flat endothelial cells with a polygonal shape, and demonstrated raised atherosclerotic lesions with increase in serum cholesterol level. In contrast, the intima of the MyoLAD was free of atherosclerotic lesions throughout the study, and the endothelial cells were spindle-shaped and engorged. While ferritin particles reached only the surroundings of the internal elastic lamina in the MyoLAD, they permeated into the media of the EpiLAD. We suggest that myocardial bridges suppress coronary atherosclerosis by an alteration of endothelial permeability, which may be due to changes in haemodynamic force tending towards a higher shear stress. The data provide an insight into the relationship between haemodynamics and the development of coronary atherosclerosis.
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
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