Search PubMed⌕ Search

Biomedical subjects

Kazunori Sato

Publications and source records attributed to Kazunori Sato.

At least 19 recordsLinked to original sources
PubMed2006

Database of normal human cerebral blood flow measured by SPECT: I. Comparison between I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD as referred with O-15 labeled water PET and voxel-based morphometry.

OBJECTIVES: Three accumulative tracers, iodine-123-labeled N-isopropyl-p-iodoamphetamine (I-123-IMP), technetium-99m-labeled hexamethylpropyleneamineoxime (Tc-99m-HMPAO), and technetium-99m-labeled ethyl cysteinate dimer (Tc-99m-ECD) are widely used to measure cerebral blood flow (CBF) in single-photon emission computed tomography (SPECT). In the present study, normal regional distribution of CBF measured with three different SPECT tracers was entered into a database and compared with regional distribution of CBF measured by positron emission tomography (PET) with H2(15)O. The regional distribution of tissue fractions of gray matter determined by voxel-based morphometry was also compared with SPECT and PET CBF distributions. METHODS: SPECT studies with I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD were performed on 11, 20, and 17 healthy subjects, respectively. PET studies were performed on 11 healthy subjects. Magnetic resonance (MR) imaging studies for voxel-based morphometry were performed on 43 of the 48 subjects who underwent SPECT study. All SPECT, PET, and MR images were transformed into the standard brain format with the SPM2 system. The voxel values of each SPECT and PET image were globally normalized to 50 ml/100 ml/min. Gray matter, white matter, and cerebrospinal fluid images were segmented and extracted from all transformed MR images by applying voxel-based morphometry methods with the SPM2 system. RESULTS: Regional distribution of all three SPECT tracers differed from that of H2150 in the pons, midbrain, thalamus, putamen, parahippocampal gyrus, posterior cingulate gyrus, temporal cortex, and occipital cortex. No significant correlations were observed between the tissue fraction of gray matter and CBF with any tracer. CONCLUSION: Differences in regional distribution of SPECT tracers were considered to be caused mainly by differences in the mechanism of retention of tracers in the brain. Regional distribution of CBF was independent of regional distribution of gray matter fractions, and consequently the blood flow per gray matter volume differed for each brain region.

Brain↗
PubMed2006

Database of normal human cerebral blood flow measured by SPECT: II. Quantification of I-123-IMP studies with ARG method and effects of partial volume correction.

UNLABELLED: The limited spatial resolution of SPECT causes a partial volume effect (PVE) and can lead to the significant underestimation of regional tracer concentration in the small structures surrounded by a low tracer concentration, such as the cortical gray matter of an atrophied brain. The aim of the present study was to determine, using 123I-IMP and SPECT, normal CBF of elderly subjects with and without PVE correction (PVC), and to determine regional differences in the effect of PVC and their association with the regional tissue fraction of the brain. METHODS: Quantitative CBF SPECT using 123I-IMP was performed in 33 healthy elderly subjects (18 males, 15 females, 54-74 years old) using the autoradiographic method. We corrected CBF for PVE using segmented MR images, and analyzed quantitative CBF and regional differences in the effect of PVC using tissue fractions of gray matter (GM) and white matter (WM) in regions of interest (ROIs) placed on the cortical and subcortical GM regions and deep WM regions. RESULTS: The mean CBF in GM-ROIs were 31.7 +/- 6.6 and 41.0 +/- 8.1 ml/100 g/min for males and females, and in WM-ROIs, 18.2 +/- 0.7 and 22.9 +/- 0.8 ml/100 g/min for males and females, respectively. The mean CBF in GM-ROIs after PVC were 50.9 +/- 12.8 and 65.8 +/- 16.1 ml/100 g/min for males and females, respectively. There were statistically significant differences in the effect of PVC among ROIs, but not between genders. The effect of PVC was small in the cerebellum and parahippocampal gyrus, and it was large in the superior frontal gyrus, superior parietal lobule and precentral gyrus. CONCLUSION: Quantitative CBF in GM recovered significantly, but did not reach values as high as those obtained by invasive methods or in the H2(15)O PET study that used PVC. There were significant regional differences in the effect of PVC, which were considered to result from regional differences in GM tissue fraction, which is more reduced in the frontoparietal regions in the atrophied brain of the elderly.

Aged↗
PubMed2005

Male elderly subthreshold depression patients have smaller volume of medial part of prefrontal cortex and precentral gyrus compared with age-matched normal subjects: a voxel-based morphometry.

BACKGROUND: The brain morphological changes in subthreshold depression (sD) have not been clarified. We examined the structural difference in regional gray matter volume between community-dwelling elderly subjects with sD and age-matched nondepressed normal subjects by voxel-based morphometry (VBM) based on magnetic resonance imaging (MRI). METHODS: Thirty-four community-dwelling elderly subjects with sD and 109 age-matched nondepressed normal subjects were studied by MRI. We defined subjects with sD as those who showed a Geriatric Depression Scale score of 15 or higher and a Mini Mental State Examination score of 22 or higher, and do not fulfill the criteria of major depressive disorder (MDD) in the Diagnostic and Statistical Manual for Mental Disorders IV. We collected brain magnetic resonance images of 34 subjects with sD and 109 age-matched normal subjects, and analyzed the difference in regional gray matter volume between these two groups by VBM. RESULTS: Male subjects with sD had significantly smaller volumes of the medial part of the bilateral frontal lobes and the right precentral gyrus than normal male subjects. LIMITATIONS: We have not clarified the discrepancy in the results of gender difference. CONCLUSIONS: Our study revealed that even community-dwelling elderly male subjects with sD show bilateral prefrontal gray matter volume reduction, which was reported to be observed in elderly patients with MDD, although there is no significant volume reduction in the hippocampus, which was also reported to be observed in MDD. Our study may contribute to clarifying the mechanism underlying brain pathological changes in sD.

Age of Onset↗
PubMed2005

Upregulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway.

BACKGROUND: A natural retinoid all-trans retinoic acid (ATRA) contains various beneficial effects on vasculature, including suppression of neointima formation after balloon injury. However, little is known about the effects of ATRA on vascular endothelial function. We therefore studied its role in nitric oxide (NO) production of vascular endothelial cells (ECs). METHODS AND RESULTS: Human dermal microvascular ECs, human umbilical vein ECs, and SV40-transformed rat lung vascular ECs were incubated with or without ATRA (1 micromol/L) for 48 hours. Their NO production was determined with the use of a fluorescent NO indicator, diaminofluorescein-2 diacetate. ATRA significantly increased their basal as well as acetylcholine-induced NO production. Treatment with Nomega-nitro-L-arginine methyl ester or carboxy-PTIO suppressed their fluorescence. Increase of NO production was also observed by incubation with retinoic acid receptor (RAR) agonist Am580. ATRA-induced NO increase was abolished by coincubation with RAR antagonist LE540. Moreover, the NO increase was completely inhibited by the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin and LY294002. ATRA as well as Am580 enhanced endothelial NO synthase (eNOS) phosphorylation at Ser-1177 as well as Akt phosphorylation at Ser-473 without changing their protein expression. Overexpression of dominant-negative Akt inhibited the eNOS phosphorylation. Moreover, ATRA increased PI3K activity as well as PI3K catalytic subunit p110beta protein expression, which was completely inhibited by LE540 treatment. Real-time polymerase chain reaction analyses demonstrated that ATRA increased PI3K catalytic subunit p110beta mRNA expression without affecting its stability. Finally, ATRA-induced NO increase was observed in COS-1 cells transfected with wild-type eNOS and RARalpha, but not with mutated eNOS whose Ser-1177 was substituted. CONCLUSIONS: ATRA increases NO production by eNOS phosphorylation through RAR-mediated PI3K/Akt pathway activation in vascular ECs and possibly plays beneficial roles in vascular endothelium. Retinoids may therefore be candidates as novel therapeutic agents against vascular disorders with endothelial damage.

Cells, Cultured↗
PubMed2005

Effects of tissue heterogeneity on cerebral vascular response to acetazolamide stress measured by an I-123-IMP autoradiographic method with single-photon emission computed tomography.

OBJECTIVES: Single-photon emission computed tomography (SPECT) with iodine-123 (123I)-labeled N-isopropyl-p-iodoamphetamine (IMP) is widely used in measuring the cerebral blood flow (CBF) response to acetazolamide stress for assessment of cerebral vascular reserve. To quantitate CBF by means of SPECT with IMP, an autoradiographic (ARG) method has been developed and is widely used. Because the relation between the brain counts on the SPECT scan and CBF is not linear in the ARG method, a mixture of gray and white matter in a pixel causes errors in the calculation of CBF. In the present study, errors in the calculation of CBF and vascular response to acetazolamide stress by the ARG method due to tissue heterogeneity were estimated by simulation study. Correction for effects of tissue heterogeneity in SPECT data was also attempted. METHODS: Images of gray and white matter fraction were obtained by voxel-based morphometry analysis of magnetic resonance (MR) imaging data set. Ideal CBF images, which were generated from gray and white matter fraction images with assumed blood flow values for gray and white matter, were compared to CBF images generated by the ARG method. Correction for effects of tissue heterogeneity in SPECT data was performed with gray and white matter fraction data obtained from MR images. RESULTS: Systematic underestimation of CBF due to tissue heterogeneity was observed in all brain regions. In the neocortical regions, underestimation by -21% to -16%, -26% to -20%, -31% to -24%, and -35% to -27% was observed for gray and white matter blood flow of 80 and 20, 100 and 25, 120 and 30, and 140 and 35 ml/100 ml/min, respectively. Vascular response was also systematically underestimated in most brain regions. Vascular responses in the neocortical regions ranged from 17% to 20%, from 31% to 37%, and from 42% to 52% when ideal vascular responses were 25%, 50%, and 75%, respectively. After correction for the effects of tissue heterogeneity, values of vascular response to acetazolamide stress ranged from 64% to 116% in the neocortical regions, whereas values obtained by the ARG method ranged from 48% to 52%. CONCLUSION: Underestimation of the vascular response to acetazolamide stress due to tissue heterogeneity should be considered in the estimation of cerebral vascular reserve.

Acetazolamide↗
PubMed2005

Apparent CBF decrease with normal aging due to partial volume effects: MR-based partial volume correction on CBF SPECT.

Several studies using single photon emission tomography (SPECT) have shown changes in cerebral blood flow (CBF) with age, which were associated with partial volume effects by some authors. Some studies have also demonstrated gender-related differences in CBF. The present study aimed to examine age and gender effects on CBF SPECT images obtained using the 99mTc-ethyl cysteinate dimer and a SPECT scanner, before and after partial volume correction (PVC) using magnetic resonance (MR) imaging. Forty-four healthy subjects (29 males and 15 females; age range, 27-64 y; mean age, 50.0 +/- 9.8 y) participated. Each MR image was segmented to yield grey and white matter images and coregistered to a corresponding SPECT image, followed by convolution to approximate the SPECT spatial resolution. PVC-SPECT images were produced using the convoluted grey matter MR (GM-MR) and white matter MR images. The age and gender effects were assessed using SPM99. Decreases with age were detected in the anterolateral prefrontal cortex and in areas along the lateral sulcus and the lateral ventricle, bilaterally, in the GM-MR images and the SPECT images. In the PVC-SPECT images, decreases in CBF in the lateral prefrontal cortex lost their statistical significance. Decreases in CBF with age found along the lateral sulcus and the lateral ventricle, on the other hand, remained statistically significant, but observation of the spatially normalized MR images suggests that these findings are associated with the dilatation of the lateral sulcus and lateral ventricle, which was not completely compensated for by the spatial normalization procedure. Our present study demonstrated that age effects on CBF in healthy subjects could reflect morphological differences with age in grey matter.

Adult↗
PubMed2005

Rectovaginal fistulas after rectal cancer surgery: Incidence and operative repair by gluteal-fold flap repair.

BACKGROUND: We investigated the correlation between operative procedures for rectal carcinoma and postoperative rectovaginal fistulas (RVF), and treatment for RVF. METHODS: The medical records of 161 female patients with rectal carcinoma were examined retrospectively with respect to the cause, incidence, and methods of treatment for RVF occurring after rectal cancer operations, and to the outcomes of gluteal-fold flap repairs for RVF. RESULTS: Of the 161 patients, 16 developed RVF clinically. The incidence of RVF was significantly higher in patients who were anastomosed by the double stapling technique (DST) and had concomitant resection of the vaginal wall. No statistical difference was found between the established diverting ostomy group and the no-stoma group. Six patients recovered by the establishment of a diverting ostomy only. The gluteal-fold flap technique was performed for 5 patients. No RVF recurrences were noted in these 5 patients. CONCLUSIONS: The incidence of RVF was higher in the patients who were anastomosed by DST or had concomitant resection of the vaginal wall. Although some RVFs heal with only fecal diversion, for patients in whom RVF is caused by involvement of the vaginal wall in the circular staple or intersphincteric resection, good results are obtained with the gluteal-fold flap repair technique.

Aged↗
PubMed2005

Perinephric angiomyolipoma: a unique development pattern surrounding the kidney.

We report a case of a 31-year-old man with extrarenal angiomyolipoma of the perinephric space. He presented with asymptomatic macrohematuria. Computed tomography of the abdomen revealed a large perinephric mass which was separated from the right kidney and its unique growth appeared to have surrounded the kidney. Extrarenal angiomyolipomas of the perinephric fat are rare and they should be considered in the differential diagnosis of a retroperitoneal mass where asymptomatic macrohematuria was presented at the onset.

Adult↗
PubMed2004

Early results of intersphincteric resection for patients with very low rectal cancer: an active approach to avoid a permanent colostomy.

PURPOSE: Abdominoperineal resection has been the standard surgery for very low rectal cancer located within 5 cm of the anal verge. However, permanent colostomy exerts serious limitations on quality of life. The present study aimed to investigate curability and functional results of intersphincteric resection and additional partial external sphincteric resection for carcinoma of the anorectal junction. METHODS: Thirty-five patients were prospectively studied from November 1999 to September 2002. All patients displayed adenocarcinoma (T3: n = 26; T2: n = 7; T1: n = 2) located between 0 and 2 cm above the dentate line. Abdominotransanal rectal resection with total mesorectal excision was performed in all patients (total intersphincteric resection: n = 14; subtotal intersphincteric resection: n = 5; additional partial external sphincteric resection: n = 6). All patients underwent diverting colostomy, which was closed at a median of six months postoperatively. Twenty patients received preoperative radiochemotherapy. RESULTS: All patients had curative intent with microscopic safety margins (mean surgical cut end: 4 mm; mean distal cut end: 10 mm). No postoperative mortality was encountered. Morbidity was identified in 13 patients (perianastomotic abscess: n = 4; anastomotic leakage and fistula: n = 4; postoperative bleeding: n = 2; wound infection: n = 1; anastomotic stenosis: n = 1; anovaginal fistula: n = 1). One of these patients received a permanent colostomy. Five patients developed recurrence (liver: n = 1; lung: n = 2; local and lung: n = 1; abdominal wall: n = 1) during the median observation period (23 months). Two of these patients underwent curative resection of liver or lung metastases. Twenty-one patients have received stoma closure, and although continence was satisfactory in all, 5 displayed occasional minor soiling 12 months after stoma closure. Anal canal manometry demonstrated significant reduction in maximum resting pressure (median: 50 cmH(2)O at 12 months after stoma closure), but acceptable function results were obtained. CONCLUSION: Curability and anal function were achieved by means of intersphincteric resection without or with additional partial external sphincteric resection. These procedures can be recommended for low rectal cancer patients who are candidates for abdominoperineal resection.

Adenocarcinoma↗
PubMed2004

Error analysis of measured cerebral vascular response to acetazolamide stress by I-123-IMP autoradiographic method with single photon emission computed tomography: errors due to distribution volume of I-123-IMP.

OBJECTIVES: Iodine-123 (123I)-labeled N-isopropyl-p-iodoamphetamine (IMP) has been used as a cerebral blood flow (CBF) tracer for single-photon emission computed tomography (SPECT), and measurements of the CBF response to acetazolamide stress by SPECT with IMP are widely used to assess cerebral vascular reserve. To quantitate CBF by means of SPECT with IMP, an autoradiographic (ARG) method has been developed and is widely used. In the ARG method, CBF is calculated from the brain counts of the SPECT scan with an assumed distribution volume value of IMP (Vd). However, differences between true Vd and assumed Vd results in errors in calculated CBF. In the present study, errors in the CBF response to acetazolamide stress as calculated by the ARG method were investigated. METHODS: SPECT studies were performed on 12 patients with steno-occlusive lesions of the major cerebral artery. Two studies were performed on separate days. The first study was performed at rest (baseline), and the second during acetazolamide stress. SPECT scans were performed at 40 min (early scan) and 180 min (delayed scan) after intravenous injection of IMP. RESULTS: Although a simulation study showed that errors in calculated changes in CBF in response to acetazolamide stress, which result from differences between the true Vd and the assumed Vd, were larger when the baseline CBF and change in CBF were larger, values calculated by the ARG method with an assumed Vd were in good agreement with those calculated with true Vd obtained from early and delayed scan data. CONCLUSION: These data indicate that errors in the calculated CBF response to acetazolamide stress as calculated by the ARG method are negligible even at high CBF responses. The ARG method is therefore reliable for measurement of CBF response to acetazolamide stress.

Acetazolamide↗
PubMed2004

Voxel-based morphometry of human brain with age and cerebrovascular risk factors.

The objectives of this study were to evaluate the correlations of the volumes of the gray matter and white matter with age, and the correlations of the tissue probabilities of the gray matter and white matter with age and several cerebrovascular risk factors. We obtained magnetic resonance (MR) images of the brain and clinical information from 769 normal Japanese subjects. We processed the MR images automatically by correcting for inter-individual differences in brain size and shape, and by segmenting the MR images into the gray matter and white matter. Volumetry of the brain revealed a significant negative correlation between the gray matter volume and age, which was not observed between white matter volume and age. Voxel-based morphometry showed that age, systolic blood pressure, and alcohol drinking correlated with the regional tissue probabilities of the gray matter and white matter.

Adolescent↗
PubMed2004

Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5-trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain.

Upon activation of cell surface receptors coupled to the Gq subclass of G proteins, phospholipase C (PLC) beta hydrolyses membrane phospholipid to yield a pair of second messengers, inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol. PLCbeta4 has been characterized as the isoform enriched in cerebellar Purkinje cells (PCs) and the retina and involved in motor and visual functions. Here we examined cellular and subcellular distributions of PLCbeta4 in adult mouse brains. Immunohistochemistry showed that high levels of PLCbeta4 were detected in the somatodendritic domain of neuronal populations expressing the metabotropic glutamate receptor (mGluR) type 1alpha, including olfactory periglomerular cells, neurons in the bed nucleus anterior commissure, thalamus, substantia nigra, inferior olive, and unipolar brush cells and PCs in the cerebellum. Low to moderate levels were detected in many other mGluR1alpha-positive neurons and in a few mGluR1alpha-negative neurons. In PCs, immunogold electron microscopy localized PLCbeta4 to the perisynapse, at which mGluR1alpha is concentrated, and to the smooth endoplasmic reticulum in dendrites and spines, an intracellular Ca2+ store gated by IP3 receptors. In the cerebellum, immunoblot demonstrated its concentrated distribution in the post-synaptic density and microsomal fractions, where mGluR1alpha and type 1 IP3 receptor were also greatly enriched. Furthermore, PLCbeta4 formed coimmunoprecipitable complexes with mGluR1alpha, type 1 IP3 receptor and Homer 1. These results suggest that PLCbeta4 is preferentially localized in the perisynapse and smooth endoplasmic reticulum as a component of the physically linked phosphoinositide signaling complex. This close molecular relationship might provide PLCbeta4 with a high-fidelity effector function to mediate various neuronal responses under physiological and pathophysiological conditions.

Animals↗
PubMed2004

Expression of peroxisome proliferator-activated receptor isoform proteins in the rat kidney.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors mediating ligand-dependent transactivation. Among the 3 isoforms, PPAR- alpha is involved in lipid metabolism in the liver, while PPAR-gamma(-gamma1 and -gamma2) is involved in adipocyte differentiation. Recently, PPARs have been suggested to be involved in renal electrolyte metabolism as well as atherosclerosis. PPAR-alpha is known to regulate cytochrome P450 gene expression, and may possibly affect sodium retention in the kidney. Moreover, PPAR-gamma is involved in the transcription regulation of blood pressure regulatory genes, including thromboxane and angiotensin II type 1 receptors. In the kidney, although expression of PPARs has been reported, detailed immunohistochemical analyses have not been performed. We here generated isoform-specific anti-PPAR antibodies to localize their proteins in the kidney. Anti-PPAR antibodies were raised against synthetic peptides. Their isoform specificity was confirmed by immunoblot analyses, immunoprecipitations, and antibody supershift experiments by electrophoretic mobility shift assay. We therefore studied the protein expression of PPARs in the kidney of adult Sprague-Dawley rats using these antibodies. Immunoblot analyses demonstrated protein expression of PPAR-alpha and -gamma1, but not of -gamma2, in the kidney nuclear extracts. Immunohistochemical analyses demonstrated that both PPAR-alpha and -gamma1 proteins were widely expressed in the nuclei of mesangial and epithelial cells in glomeruli, proximal and distal tubules, the loop of Henle, medullary collecting ducts, and intima/media of renal vasculatures. PPAR-alpha and -gamma1 proteins are thus widely expressed along the nephron segments, and may affect gene expression at these segments. Further studies will be needed to identify additional target genes for PPARs along the nephron segments.

Animals↗
PubMed2003

Regional differences between 99mTc-ECD and 99mTc-HMPAO SPET in perfusion changes with age and gender in healthy adults.

A number of studies using single-photon emission tomography (SPET) have shown perfusion changes with age in several cortical and subcortical areas, which might distort the results of perfusion imaging studies of neuropsychiatric disorders. Technetium-99m labelled ethyl cysteinate dimer (ECD) and hexamethylpropylene amine oxime (HMPAO) are both used as markers of cerebral perfusion, but have different pharmacokinetics and retention patterns. The aim of this study was to determine whether age and gender effects on perfusion SPET differ depending on whether (99m)Tc-HMPAO or (99m)Tc-ECD is used. Forty-five subjects (20 male and 25 female, mean age 52.8+/-6.6 years) were assigned to (99m)Tc-HMPAO SPET (HMPAO group), and 39 subjects (24 male and 15 female, mean age 52.6+/-6.7 years) to (99m)Tc-ECD SPET (ECD group). SPET images were obtained about 10 min after intravenous injection of approximately 800 MBq (99m)Tc-HMPAO or (99m)Tc-ECD using the same SPET scanner. Three-dimensional volumetric magnetic resonance imaging was performed to as7sess morphological changes in the grey matter. All image processing and statistical analyses were performed using SPM99 software. An area in the right anterior frontal lobe showed an increase in perfusion with age only in the HMPAO group, whereas areas in the bilateral retrosplenial cortex showed decreases in perfusion with age only in the ECD group; neither group showed corresponding changes in the grey matter. The present study shows that different effects of age on perfusion are observed depending on whether (99m)Tc-HMPAO and (99m)Tc-ECD is used. This suggests that the results of perfusion SPET are differently confounded depending on the tracer used, and that perfusion SPET with these tracers has limitations when used in research on subtle perfusion changes.

Age Factors↗
PubMed2003

Neuroanatomical database of normal Japanese brains.

To develop a high-resolution in vivo human neuroanatomy database for Japanese brains, a data set on 1547 normal subjects between the ages of 16 and 79 years has been collected. First, we determined individual reference brains of normal Japanese for each age and gender group. We found there exists cross-generational changes in brain shape, that is, the young generation has a shorter and wider brain than the older generation. Second, we determined the effect of aging on the volume of gray matter and white matter by voxel based morphometry. A significant negative correlation between the gray matter volume and age was observed. We assume that this kind of database is quite useful to investigators who are engaged in basic neuroscience, clinical diagnostics and evaluation of neuropsychiatric disorders in patients.

Adolescent↗
PubMed2003

Effects of mitogen-activated protein kinase pathway and co-activator CREP-binding protein on peroxisome proliferator-activated receptor-gamma-mediated transcription suppression of angiotensin II type 1 receptor gene.

Peroxisome proliferator-activated receptor (PPAR)-gamma and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the --58/--34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-gamma function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-gamma and modulates its activity. Since both the MAP kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-gamma-mediated AT1R gene transcription suppression. We observed that 1) PPAR-gamma-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect; 2) the PPAR-gamma-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-gamma-mediated AT1R gene transcription suppression; and 4) the CBP effect was eliminated when the --58/--34 GC-box related element was disrupted. It is therefore speculated that: 1) PPAR-gamma phosphorylation by the MAP kinase pathway may attenuate PPAR-gamma-mediated AT1R gene transcription suppression through the inhibition of PPAR-gamma activity; and 2) CBP may enhance the activity of the remaining Sp1 on the --58/--34 GC-box related element, resulting in a reduction in PPAR-gamma-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-gamma in AT1R gene transcription, probably leading to the progression of atherosclerosis.

Animals↗
PubMed2003

Transcription suppression of thromboxane receptor gene expression by retinoids in vascular smooth muscle cells.

Thromboxane (TX) A2 induces contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. Retinoids, derivatives of vitamin A, have recently been shown to be anti-atherosclerotic in VSMCs. We therefore examined the effects of retinoids on TX-induced cell growth and TXR expression in VSMCs. TX-induced VSMC proliferation assessed by 3H-thymidine incorporation was completely abrogated by all-trans retinoic acid (ATRA) treatment. The expression of TXR mRNA was significantly decreased by treatment either with ATRA or its stereoisomer 9-cis retinoic acid (RA). Transcription activity of the TXR gene promoter was suppressed by treatment with these retinoids, and a study using retinoid receptor-selective agonists demonstrated that retinoic acid receptors (RARs), rather than retinoid X receptors (RXRs), were mainly involved in the transcription suppression. Deletion analyses demonstrated that the suppression was mediated via the -22/-7 GC-box related sequence. Electrophoretic mobility shift assays showed that Sp1, but not RAR and/or RXR, could bind to the element. The formation of the Sp1-DNA complex was inhibited by co-incubation with RAR, but not by RXR. Taken together, these findings suggest that TXR gene transcription suppression may be mediated by the inhibition of Sp1 binding to the -22/-7 GC-box related sequence by activated RAR, which may result in the inhibition of TX-induced VSMC proliferation. Our study indicates a novel anti-atherosclerotic action of retinoids in VSMCs.

Alitretinoin↗