Language：English   Publisher：AMER PHYSIOLOGICAL SOC  

Focal adhesion kinase ( FAK) is important to cellular functions such as proliferation, migration, and survival of anchorage- dependent cells. We investigated the role of FAK in modulating normal cellular responses, specifically cell survival in response to inflammatory stimuli and serum withdrawal, using FAK- knockout ( FAK(-/-)) embryonic fibroblasts. FAK(-/-) fibroblasts were more vulnerable to TNF-alpha- induced apoptosis, as measured by terminal deoxynucleotidyl transferase positivity. FAK(-/-) fibroblasts also demonstrated increased procaspase- 3 cleavage to p17 subunit, whereas this was undetectable in FAK(-/-) fibroblasts. Insulin receptor substrate- 1 expression was completely abolished and NF-kappa B activity was reduced, with a concomitant decrease in abundance of the anti- apoptotic protein Bcl- x(L) in FAK(-/-) cells. Upon serum withdrawal, FAK(-/-) cells exhibited marked attenuation of basal ERK phosphorylation, while FAK(-/-) cells, in contrast, maintained high basal ERK phosphorylation. Moreover, inhibition of ERK phosphorylation potentiated serum withdrawal- induced caspase- 3 activity. This was paralleled by increased insulin receptor substrate ( IRS)- 2 expression in FAK(-/-) cells, although both insulin- and IGF-1-mediated phosphorylation of Akt/ PKB and GSK-3 were impaired. This suggests that IRS-2 protects against apoptosis upon serum withdrawal via the ERK signaling pathway. The specific role of FAK to protect cells from apoptosis is regulated by activation and phosphorylation of NF-kappa B and interaction between activated growth factor anti-apoptotic signaling pathways involving both phosphatidylinositol 3- kinase/ Akt and MAPK/ ERK1/2. We demonstrate that FAK is necessary for upregulation of the anti- apoptotic NF-kappa B response, as well as for normal expression of growth factor signaling proteins. Thus we propose a novel role for FAK in protection from cytokine- mediated apoptosis.

DOI： 10.1152/ajpcell.00144.2006

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C-reactive protein (CRP), the prototypical human acute phase protein, is an independent risk predictor of future cardiovascular events, both in healthy individuals and in patients with known cardiovascular disease. In addition, previous studies indicate that CRP might have direct proatherogenic properties. Ligand activation of the liver X receptor (LXR), a member of the nuclear hormone receptor superfamily, inhibits inflammatory gene expression in macrophages and attenuates the development of atherosclerosis in various animal models. We demonstrate herein that 2 synthetic LXR ligands, T0901317 and GW3965, inhibit interleukin-1 beta/interleukin-6-induced CRP mRNA and protein expression in human hepatocytes. Knockdown of LXR alpha/beta by short interfering RNAs completely abolished the inhibitory effect of the LXR agonist T0901317 on cytokine-induced CRP gene transcription. Transient transfection experiments with 5'-deletion CRP promoter constructs identified a region from -125 to -256 relative to the initiation site that mediated the inhibitory effect of LXR ligands on CRP gene transcription. Depletion of the nuclear receptor corepressor by specific short interfering RNA increased cytokine-inducible CRP mRNA expression and promoter activity and reversed LXR ligand-mediated repression of CRP gene transcription. Chromatin immunoprecipitation assays indicated that nuclear receptor corepressor is present on the endogenous CRP promoter under basal conditions. Cytokine-induced clearance of nuclear receptor corepressor complexes was inhibited by LXR ligand treatment, maintaining the CRP gene in a repressed state. Finally, treatment of C57B16/J mice with LXR ligands attenuated lipopolysaccharide-induced mouse CRP and serum amyloid P component gene expression in the liver, whereas no effect was observed in LXR alpha beta knockout mice. Our observations identify a novel mechanism of inflammatory gene regulation by LXR ligands. Thus, inhibition of CRP expression by LXR agonists may provide a promising approach to impact initiation and progression of atherosclerosis.

DOI： 10.1161/01.RES.0000252878.34269.06

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. The 3 PPAR isotypes, PPAR-alpha, PPAR-gamma, and PPAR-delta, play a key role in the regulation of lipid and glucose metabolism. Obesity and the interrelated disorders of the metabolic syndrome have become a major worldwide health problem. In this review, we summarize the critical role of PPARs in regulating inflammation, lipoprotein metabolism, and glucose homeostasis and their potential implications for the treatment of obesity, diabetes, and atherosclerosis.

DOI： 10.1161/01.ATV.0000191663.12164.77

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：ELSEVIER SCI LTD  

The metabolic syndrome is a worldwide epidemic, setting the stage for type 2 diabetes and its microvascular complications, and acceleration of macrovascular disease. Insulin resistance, hyperglycemia, dyslipidemia, hypertension, thrombotic disorders and adiposity define the metabolic syndrome and contribute to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Angiotensin II contributes to the development and progression of cardiovascular and renal endpoints and, as such, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors demonstrate a protective effect. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR gamma), appear to impact favourably on atherosclerosis through both direct and indirect mechanisms. In humans, these ligands improve endothelial function, attenuate albuminuria and hypertension, and potentially prevent conversion of prediabetes to type 2 diabetes. Statins also have proven benefit in decreasing overall cardiovascular and stroke mortality and morbidity. The combination of angiotensin II blockade, statin therapy and PPAR gamma activation might emerge as an important global therapeutic strategy in the metabolic syndrome and diabetes. Further studies are needed to determine whether they have synergistic effects to protect the vasculature.

DOI： 10.1016/j.coph.2005.01.008

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

Cyclooxygenase 2 (COX-2) inhibitors are promising antiangiogenic agents in several preclinical models. The aim of the present study was to evaluate the effect of selective COX-2 inhibitors on vascular endothelial growth factor (VEGF) production in vitro and angiogenesis and growth of pancreatic cancer in vivo, focusing on putative differences between COX-2-negative and COX-2-positive tumors. VEGF production and angiogenesis in vitro were determined by ELISA and endothelial cell migration assay. To determine whether the effect of COX-2 inhibitors was mediated by peroxisome proliferator-activated receptor gamma (PPAR-gamma), we used a dominant-negative PPAR-gamma and a pharmacologic inhibitor. In vitro findings were validated in a pancreatic cancer animal model. Microvessel density was assessed by CD31 immunostaining. Intratumoral prostaglandin and VEGF levels were measured by mass spectroscopy and ELISA. Selective COX-2 inhibitors had a concentration-dependent effect on VEGF production in vitro. Higher concentrations increased VEGF levels and stimulated angiogenesis by activating PPAR-gamma. In vivo, nimesulide increased VEGF production by cancer cells in COX-2-positive and COX-2-negative pancreatic tumors. In COX-2-negative pancreatic cancer, this effect was associated with an increase in angiogenesis and growth. In COX-2-positive pancreatic cancer, the nimesulide-induced increase of VEGF production by the cancer cells was offset by a decrease in VEGF production by the nonmalignant cell types leading to reduced tumor angiogenesis and growth. Selective COX-2 inhibitors had opposite effects on growth and angiogenesis in pancreatic cancer depending on COX-2 expression. These findings imply that assessing the COX-2 profile of the pancreatic tumor is mandatory before initiating therapy with a selective COX-2 inhibitor.

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DOI： 10.1161/01.CIR.0000136999.77584.A2

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DOI： 10.1161/01.CIR.0000136999.77584.A2

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-gamma gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-8 plays a pivotal role in transactivation of PPAR-,y gene. It has been well known that the interaction between C/EBPs and PPAR-gamma plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-gamma and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-5 expression induced by inflammation positively regulated transcription and protein expression of PPAR-gamma in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-gamma ligands troglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited IL-1beta-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-gamma ligands inhibited IL-1beta-induced transactivation of IL-6 gene via suppression of not only nuclear factor-kappaB but also C/EBP-DNA binding. Moreover, PPAR-gamma ligands suppressed protein expression and transcription of C/EBP-5 through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-5 is negatively autoregulated via transactivation of PPAR-gamma. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.

DOI： 10.1161/01.RES.0000031271.20771.4F

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-gamma gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-8 plays a pivotal role in transactivation of PPAR-,y gene. It has been well known that the interaction between C/EBPs and PPAR-gamma plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-gamma and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-5 expression induced by inflammation positively regulated transcription and protein expression of PPAR-gamma in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-gamma ligands troglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited IL-1beta-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-gamma ligands inhibited IL-1beta-induced transactivation of IL-6 gene via suppression of not only nuclear factor-kappaB but also C/EBP-DNA binding. Moreover, PPAR-gamma ligands suppressed protein expression and transcription of C/EBP-5 through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-5 is negatively autoregulated via transactivation of PPAR-gamma. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.

DOI： 10.1161/01.RES.0000031271.20771.4F

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Background The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis.
Objective To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients.
Patients and main outcome measures Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay.
Results Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r = 0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030).
Conclusions These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension. J Hypertens 20:895-898 (C) 2002 Lippincott Williams Wilkins.

DOI： 10.1097/00004872-200205000-00024

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Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Oxidative stress plays a critical role in normal functioning of cardiac and vascular cells as well as in the pathogenesis of cardiovascular disease. Growth arrest and DNA damage-inducible gene 153 (GADD153), which is upregulated by oxidative stress, regulates the cell cycle and apoptosis. Previously an AP-1 was reported to contribute significantly to GADD153 gene transcriptional activation by oxidative stress. Recently, we have reported that GADD153 gene promoter activity is negatively regulated by nuclear factor 1 (NF1), in vascular smooth muscle cells (VSMCs). The aim of this study was to elucidate the roles of AP-1 and NF1 in GADD153 gene induction by oxidative stress in VSMCs. H2O2 induced GADD153 mRNA and reduced NF1 mRNA expression. In the electromobility shift assay, H2O2 induced AP-1-binding activity and reduced NF1-binding activity. Overexpression of NF1 significantly suppressed the induction of the GADD153 gene after treatment with H2O2. These results revealed that induction of the GADD153 gene by oxidative stress is regulated mainly by two nuclear factors, NF1 and AP-1. (C) 2002 Elsevier Science (USA).

DOI： 10.1006/bbrc.2002.6336

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Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, the PDGF receptor. The PDGF alpha -receptor (PDGF alphaR) plays an important role in the growth and proliferation of vascular smooth muscle cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFaR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGF alphaR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and we have also suggested that C/EBP-delta is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFaR gene in VSMCs. To explore the definitive roles of C/EBP-delta protein on PDGFaR gene transcription in VSMCs, we developed C/EBP-delta transgenic rats by using a chimeric fusion gene of the mouse smooth muscle a-actin promoter and an entire coding region of rat C/EBP-delta cDNA. This report describes the first successful targeted overexpression of C/EBP-delta capable of inducing PDGFaR gene transcription and modifying cell proliferative activity to PDGFs. Targeted overexpression of C/EBP-delta evokes high levels of PDGFaR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained reveal evidence of a new role and new functional significance of C/EBP-delta on VSMC growth via the PDGFaR during the process of vascular remodeling and atherosclerosis.

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Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, the PDGF receptor. The PDGF alpha -receptor (PDGF alphaR) plays an important role in the growth and proliferation of vascular smooth muscle cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFaR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGF alphaR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and we have also suggested that C/EBP-delta is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFaR gene in VSMCs. To explore the definitive roles of C/EBP-delta protein on PDGFaR gene transcription in VSMCs, we developed C/EBP-delta transgenic rats by using a chimeric fusion gene of the mouse smooth muscle a-actin promoter and an entire coding region of rat C/EBP-delta cDNA. This report describes the first successful targeted overexpression of C/EBP-delta capable of inducing PDGFaR gene transcription and modifying cell proliferative activity to PDGFs. Targeted overexpression of C/EBP-delta evokes high levels of PDGFaR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained reveal evidence of a new role and new functional significance of C/EBP-delta on VSMC growth via the PDGFaR during the process of vascular remodeling and atherosclerosis.

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CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-α and platelet-derived growth factor-α receptor (PDGFαR). Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs). In the present study, we clarified a functional relationship between C/EBPs and PPARγ in the regulation of IL-1β-induced PDGFαR expression in VSMCs. PPARγ activators, troglitazone and 15-deoxy-Δ12,14-prostaglandin J2, inhibited IL-1β-induced PDGFαR expression and suppressed PDGF-induced proliferation activity of VSMCs. Electromobility shift and supershift assays for a C/EBP motif in the PDGFαR promoter region revealed that PPARγ activators suppressed IL-1β-induced DNA binding activity of C/EBPδ and β. PPARγ activators also suppressed IL-1β-induced C/EBPδ expression. In contrast, overexpression of C/EBPδ reversed the suppressive effect of PPARγ activators on PDGFαR expression almost completely. From these results, we conclude that the inhibitory effect of PPARγ activators on PDGFαR expression is mainly mediated by C/EBPδ suppression. Regulation of CfEBPδ by PPARγ activators probably plays critical roles in modulating inflammatory responses in the arterial wall.

DOI： 10.1074/jbc.M011655200

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Language：English   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-alpha, and platelet-derived growth factor-alpha receptor (PDGF alphaR), Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs), In the present study, we clarified a functional relationship between C/EBPs and PPAR gamma in the regulation of IL-1 beta -induced PDGF alphaR expression in VSMCs, PPAR gamma activators, troglitazone and 15-deoxy-Delta (12,14)-prostaglandin J(2), inhibited IL-1 beta -induced PDGF alphaR expression and suppressed PDGF-induced proliferation activity of VSMCs, Electromobility shift and supershift assays for a C/EBP motif in the PDGF alphaR promoter region revealed that PPAR gamma activators suppressed IL-1 beta -induced DNA binding activity of C/EBP delta and beta. PPAR gamma activators also suppressed IL-1 beta -induced C/EBP delta expression. In contrast, overexpression of C/EBP delta reversed the suppressive effect of PPAR gamma activators on PDGF alphaR expression almost completely. From these results, we conclude that the inhibitory effect of PPAR gamma activators on PDGF alphaR expression is mainly mediated by C/EBP delta suppression. Regulation of C/EBP delta by PPAR gamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.

DOI： 10.1074/jbc.M011655200

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GADD153 (growth arrest- and DNA damage-inducible gene 153) is expressed at very low levels in growing cells, but is markedly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to genotoxic agents and other growth-arresting situations. Forced expression of GADD153 induces cell cycle arrest in many types of cells. It is also reported that GADD153 is directly associated with apoptosis. Recently we have reported that platelet-derived growth factor (PDGF)-BB induces apoptosis in cultured vascular smooth muscle cells (VSMC), but only when 100% confluency is reached. These results suggested that cell-cell contact inhibition (cell growth arrest) may be a critical factor for induction of VSMC apoptosis by PDGF-BB. In the present study, we explored the role of GADD153, one of a number of growth-arrest-related gene products, in the molecular mechanisms of VSMC apoptosis in vitro and in vivo. GADD153 was markedly induced at both the mRNA and protein levels, in parallel with the induction of VSMC apoptosis, after treatment with PDGF-BB. Moreover, overexpression of GADD153 in VSMC significantly reduced cell viability and induced apoptosis. In the carotid artery balloon injury model in rats, GADD153 protein was expressed in apoptotic VSMC which were positively stained by in situ DNA labelling. These results demonstrate an important role for GADD153 in the molecular mechanisms of VSMC apoptosis.

DOI： 10.1042/CS20000220

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DOI： 10.1016/S0014-2999(00)00758-5

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DOI： 10.1016/S0014-2999(00)00758-5

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：EXCERPTA MEDICA INC  

Increased left ventricular (LV) mass and abnormal geometry have a powerful prognostic value for cardiovascular morbidity and mortality including stroke. However, there have been no studies on the association between LV hypertrophy and preclinical brain damage in essential hypertensive patients. In the present study, we investigated the relation between LV hypertrophy and asymptomatic cerebrovascular damage identified;I by magnetic resonance imaging in 150 essential hypertensive patients, with an emphasis on LV geometry. Patients were divided into the following 4 groups according to their LV mass index and relative wall thickness; normal ventricular geometry (n = 50), concentric remodeling (n = 22), eccentric hypertrophy (n = 44), and concentric LV hypertrophy (n = 34). Lacunar lesions and leukoaraiosis were evaluated. The prevalence of lacunae was significantly higher in patients with LV remodeling than in patients with normal LV (chi-square 19.6, p = 0.0002). The number of lacunae was significantly higher in patients with LV hypertrophy than in patients with normal LV or concentric remodeling (F [3,146] = 8.03, p<0.0001). The severity of leukoaraiosis was also significantly greater in patients with LV hypertrophy than in patients with a normal left ventricle (chi-square 14.5, p = 0.02). Stepwise regression analysis confirmed that LV mass index and relative wall thickness, in addition to age and systolic blood pressure, were independent predictors for asymptomatic cerebrovascular damage, even in the absence of neurologic abnormalities. In hypertensive patients, LV hypertrophy, and especially concentric LV hypertrophy, provides important prognostic information on the presence of preclinical brain damage. (C)1999 by Excerpta Medica, Inc.

DOI： 10.1016/S0002-9149(98)00870-4

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Platelet-derived growth factor (PDGF) and its receptors are widely expressed in several tissues in the stage of cellular growth and development. In adulthood, PDGF beta-receptor (PDGF beta R) is mainly detected in pathological conditions such as atherosclerotic lesions and injured vascular wall. The purpose of the present study was to elucidate the underlying mechanism of PDGF beta R gene expression under pathological conditions in vascular smooth muscle cells (VSMC) and to identify the important cis elements responsible for tissue-specific gene transcription. Cel mobility shift assay and supershift assay indicated that the CCAAT motif located at -67 (C67) was mainly interacted with NF-YC, and this element drove the basal promoter activity of the gene as a putative promoter. On the other hand, another important sequence essential for the basal transcription was found at a 30-bp region (R30) spanning -150 to -121. To test whether R30 actually regulates the tissue-specific transcription of PDGF beta R gene, electromobility shift pattern was compared between VSMC and hepatoma cell line (HTC). We obtained the result that DNA-protein complex seen only in nuclear extracts from HTC suppressed the promoter activity in HTC in a tissue-specific manner. Furthermore, cis element decoy transfection experiments for C67 and R30 also revealed that both elements were functionally important in mRNA expression of PDGF beta R in VSMC. From these results, we concluded that the basal activity of PDGF beta R gene expression was transactivated by the interaction or coordination of both C67 and R30, and the latter one mainly controlled the tissue-specific gene expression in VSMC.

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To elucidate the relationship between postprandial hypotension (PPH) and asymptomatic cerebrovascular damage, we evaluated changes in blood pressure after a meal by 24-hour blood pressure monitoring in 70 hospitalized essential hypertensive patients aged greater than or equal to 50 years. They received a diet containing standard nutritional ingredients with 120 mmol (7 g) NaCl and were free from medication for at least 1 week. PPH was defined as the mean reduction of systolic blood pressure during 2 hours after a meal. Patients were divided into three groups according to mean values of PPH after 3 meals: PPH-1 (n=16, 5 mm Hg less than or equal to PPH<10 mm Hg), PPH-2 (n=18, PPH greater than or equal to 10 mm Hg), and normal (n=36, PPH<5 mm Hg). As asymptomatic cerebrovascular damage, lacunae and leukoaraiosis were evaluated by magnetic resonance imaging. PPH did not correlate with daytime or nighttime blood pressure or the nondipper phenomenon; however, PPH was significantly related to asymptomatic cerebrovascular damage. The prevalence of lacunae in the normal, PPH-1, and PPH-2 groups was 44%, 69%, and 83%, respectively (chi(2)=8.22, P<0.05). The number of lacunae in the normal, PPH-1, and PPH-2 groups was 1.0+/-1.3, 1.3+/-1.2, and 1.9+/-1.4, respectively (F[2,67]=3.2, P<0.05). The prevalence of advanced leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 44%, 50%, and 83%, respectively (chi(2)=7.63, P<0.05). Severity score of leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 1.5+/-0.7, 1.7+/-0.8, and 2.1+/-0.7, respectively (F[2,67]=4.3, P<0.05). These findings indicate that elderly hypertensive patients with marked PPH should be considered to have advanced cerebrovascular damage even in the absence of abnormal neurological findings.

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To elucidate whether postprandial hypotension (PPH) is associated with any diurnal change of blood pressure, ambulatory blood pressure monitoring was performed on 121 hospitalized essential hypertensive patients who received standardized meals, Postprandial change in blood pressure was defined as the difference between mean systolic blood pressure (SBP) 1h before and 2 h after each meal, The! postprandial decline of SEP showed age-dependent augmentation. The degree of PPH was significantly related to the level of preprandial blood pressure for each meal.
Patients were divided into the following three groups according to the mean PPH of three meals: Normal group (n = 79); mean postprandial decline of SBP <5 mm Hg, PPM-1 group (n = 24); 5 mm Hg less than or equal to mean PPH < 10 mm Mg, and PPH-2 group (n = 18); PPH greater than or equal to 10 mm Hg. There was no difference in 24-h, nighttime, or daytime blood pressure among the three groups. The prevalence of dipper and nondipper patients was not different among the three groups. However, patients in PPH-2 showed significantly greater daytime and 24-h blood pressure variability. Furthermore, there was a significant positive relationship between the morning surge of SEP and PPH after breakfast (r = 0.36, P <.001).
These findings indicate that PPH increases blood pressure variability independently of nocturnal change in blood pressure. (C) 1998 American Journal of Hypertension, Ltd.

DOI： 10.1016/S0895-7061(98)00161-7

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Objective To understand the regulatory mechanism of platelet-derived growth factor beta-receptor gene expression.
Methods A 1.7 kb genomic fragment was obtained from a rat genomic library. After we had determined an entire sequence of this fragment, transcription start sites were determined both by primer extension analysis and by riboprobe mapping. We performed a functional promoter assay by using a dual-luciferase reporter system. Progressive 5'-deletions of the fragment and site-directed mutagenesis for the CCAAT motif located at -67 or -94 were used for the assay, and their promoter activities in vascular smooth muscle cells were assessed. Gel-mobility shift analysis was also performed for the CCAAT motif at -67. Effects of the upstream sequence spanning -310 through -120 on heterologous gene promoters were also investigated.
Results Multiple transcription start sites were observed in the 5'-flanking region, and the 1.7 kb sequence was actually active as a functional promoter in vascular smooth muscle cells. Two important sequences responsible for the basal transcriptonal activity were identified by the functional promoter assay. One was the CCAAT motif at -67 which acts as a promoter itself, and the other was the upstream region spanning -310 through -210 which positively regulates the basal promoter activity.
Conclusion The basal promoter activity of the rat platelet-derived growth factor beta-receptor gene is mainly regulated by the interaction or coordination of two sequences, the CCAAT motif and the upstream control element. (C) 1998 Lippincott Raven Publishers.

DOI： 10.1097/00004872-199816040-00005

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