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Biomedical subjects

R Nagai

Publications and source records attributed to R Nagai.

At least 109 records · Page 6Linked to original sources
PubMed2001

Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and myocardial infarction in Japanese. An approach entailing melting curve analysis with specific fluorescent hybridization probes.

The platelet-collagen receptor, glycoprotein Ia/IIa (integrin alpha2beta1) plays a fundamental role in the adhesion of platelets to fibrillar collagen, an event leading to platelet activation and thrombus formation and contributing to the pathogenesis of thrombotic disease. Further, glycoprotein Ia/IIa receptor density and function may be associated with two linked and silent polymorphisms (807C/T and 873G/A) within the glycoprotein Ia gene. We tested the extent to which these polymorphisms serve as genetic markers of myocardial infarction in a Japanese population. A case-control study was carried out using 210 Japanese myocardial infarction patients and 420 age- and sex-matched controls. Genotyping was accomplished using PCR followed by melting curve analysis with specific fluorescent hybridization probes. The 807CC, CT, TT genotypes linked perfectly to the 873GG, GA, AA genotypes, respectively. Allele frequencies of the 807T (873A) variant were similar in the control and patient groups (0.373 vs. 0.352). The 807T and 873A variants of platelet glycoprotein Ia gene are common and in a perfect linkage in the Japanese population, but it appears unlikely that the 807T (873A) variant represents a useful marker of increased risk for myocardial infarction.

Adult↗
PubMed2001

[Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension].

BACKGROUND: It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet. METHODS AND RESULTS: In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg every second day) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg every second day but not with 0.01 mg/kg every second day of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment. CONCLUSIONS: These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Animals↗
PubMed2001

Anthracycline-induced cardiomyopathies evaluated by tissue Doppler tracking system and strain rate imaging.

OBJECTIVES: Anthracycline cardiotoxicity is known to occur from the subendocardial side of the left ventricular wall. Recent advances of tissue Doppler echocardiography may allow the evaluation of anthracycline cardiotoxicity by dividing the left ventricular wall into the subendocardial half and subepicardial half. The present study assessed the feasibility using the tissue Doppler echo tracking system (M-mode) and myocardial strain rate imaging (B-mode) to noninvasively detect anthracycline cardiotoxicity. METHODS: The tissue Doppler echo tracking system (M-mode) was used to measure systolic thickening of the subendocardial layer (delta Endo), subepicardial layer (delta Epi), and whole wall (delta Total) of the left ventricular posterior wall in 41 normal subjects and three groups of patients receiving anthracycline: 34 patients in the low dose group, 19 in the middle dose group, and 12 in the high dose group. Strain rate is the spatial gradient of local velocities, reflecting local compression and expansion rates not affected by overall heart motion. Myocardial strain rate imaging (B-mode) was used in 25 normal subjects, 9 patients in the low dose group, and 10 patients in the high dose group. The ratio of peak systolic strain rate of subendocardium to that of subepicardium (peak strain rate endo/epi), and the ratio of integrated strain rate during ejection time of subendocardium to that of subepicardium (integrated strain rate endo/epi) were measured. RESULTS: Tissue Doppler echo tracking system (M-mode) measurement of delta Endo/delta Epi showed the most distinct difference and the least overlap of the data between normal subjects and patients, whereas delta Total failed to show significant differences. Myocardial strain rate imaging (B-mode) measurement of integrated strain rate endo/epi showed the most distinct difference and the least overlap of the data between normal subjects and patients, but ejection fraction failed to show statistically significant differences. CONCLUSIONS: These methods are highly sensitive tools for monitoring anthracycline cardiotoxicity.

Anthracyclines↗
PubMed2001

Troglitazone improves whole-body insulin resistance and skeletal muscle glucose use in type II diabetic patients.

UNLABELLED: Recently, troglitazone has emerged as an insulin sensitizer for the treatment of type II diabetes. However, its effect on skeletal muscle glucose use (SMGU) has not been studied. METHODS: To investigate the effect of troglitazone on SMGU in patients with type II diabetes, we undertook skeletal muscle (18)F-FDG PET dynamic imaging under insulin clamping before and after administration of SMGU to 20 patients with type II diabetes. Data were compared with those for 12 age-matched healthy volunteers. RESULTS: The whole-body glucose disposal rate (GDR) was significantly lower in patients (29.9 +/- 9.83 micromol/min/kg) than in control subjects (55.6 +/- 16.5 micromol/min/kg, P < 0.01), as was the SMGU (patients, 3.27 +/- 2.17 micromol/min/kg; control subjects, 10.9 +/- 6.4 micromol/min/kg; P < 0.01). After the therapy, GDR significantly improved in patients (29.3 +/- 14.6 micromol/min/kg, P < 0.05), as did SMGU (5.06 +/- 2.11 micromol/min/kg, P < 0.05). When results for patients with and without hypertension were separately analyzed, a significant improvement in SMGU after troglitazone was seen in both normotensive and hypertensive patients (normotensive [n = 10]: baseline, 3.67 +/- 2.89 micromol/min/kg; after therapy, 5.28 +/- 2.61 micromol/min/kg; P < 0.05; hypertensive [n = 10]: baseline, 2.89 +/- 1.22 micromol/min/kg; after therapy, 4.72 +/- 1.39 micromol/min/kg; P < 0.05). GDR in patients with and without hypertension was significantly improved by troglitazone (normotensive: baseline, 17.9 +/- 10.2 micromol/min/kg; after therapy, 31.9 +/- 15.9 micromol/min/kg; P < 0.01; hypertensive: baseline, 39.6 +/- 15.1 micromol/min/kg; after therapy, 47.7 +/- 23.8 micromol/min/kg; P < 0.05). The plasma free fatty acid concentration during insulin clamping was not changed by troglitazone (baseline, 1.1 +/- 0.86 mEq/L; after therapy, 0.93 +/- 0.65 mEq/L; P = not significant). CONCLUSION: Troglitazone can improve whole-body insulin resistance through the improvement of SMGU but not through a decline in plasma free fatty acid concentration in patients with type II diabetes with or without hypertension.

Blood Glucose↗
PubMed2001

Smooth muscle cell proliferation at the vascular anastomotic stricture in rat aortotomy model.

BACKGROUND: We recently suggested that a rat aortotomy model could be substituted for a vascular anastomotic stricture around a suture line. The aim of this study was to verify such a rat aortotomy model using proliferating cell nuclear antigen (PCNA) immunohistochemistry, which is a sensitive method for detection of proliferating cells in vascular tissue after injury. METHODS: Longitudinal aortotomy was performed in the abdominal aorta of the rat subjects. The rats were sacrificed at 1, 2, 4 and 8 weeks following aortotomy (n=20 in each group). The control rats were sacrificed without aortotomy (n=20). The percentage of the lumen occluded by intimal thickening (I/M ratio) was calculated. All tissues were stained with antibodies against proliferating cell nuclear antigen (PCNA). RESULTS: Values of I/M ratio were 8.5+/-4.4%, 15.6+/-9.5%, 11.8+/-5.5%, 9.6+/-6.2% at 1, 2, 4, 8 weeks following aortotomy in the injured groups and 0.4+/-0.1% in the controls, respectively. Those values in the injured group increased significantly as compared to the controls. There were also significant differences between one week and two weeks following aortotomy. The PCNA labeling index at one week following aortotomy (21.4+/-2.7%) was significantly higher than at two weeks following aortotomy (2.8+/-1.9%). SMCs in the intima at four and eight weeks following aortotomy were completely negative for PCNA. CONCLUSIONS: The experimental rat aortotomy model was determined to be useful in the investigation of intimal thickening around the suture line.

Anastomosis, Surgical↗
PubMed2000

Induction of heme oxygenase-1 can act protectively against cardiac ischemia/reperfusion in vivo.

Enhanced production of reactive oxygen species plays a role in myocardial injury following ischemia/reperfusion. Heme oxygenase-1 (HO-1) is a heme-catabolizing enzyme that is induced by and acts against oxidant-induced tissue injury. We examined whether HO-1 expression was regulated following ischemia and reperfusion in the rat heart. HO-1 expression increased as early as 24 h after reperfusion. Strong HO-1 expression was seen in monocytes/macrophages and myofibroblasts. Next, we examined whether the induction of HO-1 could ameliorate cardiac injury following ischemia/reperfusion. Intraperitoneal hemin injection (30 mg/kg/day) for 2 days prior to the operation resulted in an about 2.8-fold increase in HO-1 expression in the rat heart. Hemin treatment significantly decreased infarct area (6 +/- 2%) compared to the control (21 +/- 2%), which was reversed by the coadministration of an HO inhibitor in a dose-dependent manner. Our data suggest that induction of HO-1 can reduce the cardiac injury in vivo following ischemia/reperfusion.

Animals↗
PubMed2000

Inducible expression of basic transcription factor-binding protein 2 (BTEB2), a member of zinc finger family of transcription factors, in cardiac allograft vascular disease.

BACKGROUND: We have recently identified basic transcription factor-binding protein 2 (BTEB2), which is involved in phenotypic modulation of vascular vascular smooth muscle cells. The aim of this study was to investigate the expression of BTEB2 in cardiac allograft vascular disease. METHODS: Heterotopic cardiac transplantation was performed in rats. All grafts were stained with antibodies against for BTEB2 and cyclin-dependent kinase 4 for immunohistochemical study. The intensity of BTEB2 expression was also calculated. RESULTS: In the allografts at 4 and 8 weeks after transplantation, smooth muscle cells were positive for BTEB2 in the diffusely thickened coronary arteries and the perivascular space. BTEB2 expression was closely associated with cyclin-dependent kinase 4 expression. The BTEB2 expression score was significantly higher in the allografts compared with the isografts. CONCLUSIONS: The induced expression of BTEB2 may play a potential role in the development of the cardiac allograft vascular disease.

Animals↗
PubMed2000

Insulin prevents cardiomyocytes from oxidative stress-induced apoptosis through activation of PI3 kinase/Akt.

BACKGROUND: Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Reactive oxygen species induce apoptosis in many types of cells including cardiomyocytes. Because insulin has been reported to have protective effects, we examined whether insulin prevents cardiomyocytes from oxidative stress-induced apoptotic death. METHODS AND RESULTS: Cultured cardiomyocytes of neonatal rats were stimulated by hydrogen peroxide (H(2)O(2)). Apoptosis was evaluated by means of the TUNEL method and DNA laddering. Incubation with 100 micromol/L H(2)O(2) for 24 hours increased the number of TUNEL-positive cardiac myocytes (control, approximately 4% versus H(2)O(2), approximately 23%). Pretreatment with 10(-)(6) mol/L insulin significantly decreased the number of H(2)O(2)-induced TUNEL-positive cardiac myocytes (approximately 12%) and DNA fragmentation induced by H(2)O(2). Pretreatment with a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin, and overexpression of dominant negative mutant of PI3K abolished the cytoprotective effect of insulin. Insulin strongly activated both PI3K and the putative downstream effector AKT: Moreover, a proapoptotic protein, BAD:, was significantly phosphorylated and inactivated by insulin through PI3K. CONCLUSIONS: These results suggest that insulin protects cardiomyocytes from oxidative stress-induced apoptosis through the PI3K pathway.

Animals↗
PubMed2000

Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor class A.

Previous studies with peritoneal macrophages obtained from macrophage scavenger receptor class A (MSR-A) knock-out mice showed that the endocytic uptake of advanced glycation end products (AGE) by macrophages was mediated mainly by MSR-A. However, it is controversial whether the endocytic uptake of intravenously injected AGE proteins by liver sinusoidal endothelial cells (LECs) is similarly explained by receptor-mediated endocytosis via MSR-A. The present study was conducted to compare the capacity to endocytose AGE proteins in LECs and peritoneal macrophages obtained from MSR-A knock-out and littermate wild-type mice. The endocytic degradation capacity of MSR-A knock-out LECs for AGE-BSA was indistinguishable from that of wild-type LECs, whereas that of MSR-A knock-out peritoneal macrophages for AGE-BSA was decreased to 30% of that in wild-type cells. Similarly, the endocytic degradation of MSR-A knock-out LECs for acetylated low-density lipoprotein (acetyl-LDL) did not differ from that of wild-type LECs, whereas the endocytic degradation of acetyl-LDL by MSR-A knock-out peritoneal macrophages was less than 20% of that in wild-type cells. Furthermore, formaldehyde-treated serum albumin (f-Alb), a ligand known to undergo scavenger-receptor-mediated endocytosis by LECs, was effectively taken up by MSR-A knock-out LECs at a capacity that did not differ from that of wild-type LECs. Moreover, the endocytic uptake of AGE-BSA by LECs was effectively competed for by unlabelled f-Alb or acetyl-LDL. These results indicate that the scavenger-receptor ligands AGE proteins, acetyl-LDL and f-Alb are endocytosed by LECs through a non-MSR-A pathway.

Animals↗
PubMed2000

Regulated expression of the BTEB2 transcription factor in vascular smooth muscle cells: analysis of developmental and pathological expression profiles shows implications as a predictive factor for restenosis.

BACKGROUND: We have previously shown BTEB2, a Krüppel-like zinc finger transcription factor, to regulate expression of the SMemb/NMHC-B gene, which has been implicated in phenotypic modulation of smooth muscle cells (SMCs). The present study was done to assess the developmental and pathological expression profiles of BTEB2 and to further evaluate the clinical relevance of BTEB2 expression in human coronary artery disease. METHODS AND RESULTS: Immunohistochemistry showed developmentally regulated expression of BTEB2 with abundant expression in fetal but not in adult aortic SMCs of humans and rabbits. In balloon-injured aortas, predominant expression of BTEB2 was seen in neointimal SMCs. Atherectomy specimens obtained from primary and restenotic lesions showed predominant expression of BTEB2 to stellate SMCs. The incidence of restenosis in primary lesions was significantly higher in lesions containing BTEB2-positive cells than in lesions without (55.6% versus 25.0%, P:=0.01). CONCLUSIONS: The present study shows that BTEB2 expression is developmentally and pathologically regulated. BTEB2 is preferentially expressed in dedifferentiated or activated SMCs. Examination of human coronary artery specimens suggests that primary lesions containing BTEB2-positive cells are associated with higher risk of restenosis than BTEB2-negative lesions. These results suggest that BTEB2 can serve as a molecular marker for phenotypic modulation of vascular SMCs.

Adult↗
PubMed2000

Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease.

A homeodomain-containing transcription factor Csx/Nkx-2.5 is an important regulator of cardiogenesis in mammals. Three different mutants, Gln170ter (designated A) and Thr178Met (designated B) in the helix 2 of the homeodomain and Gln198ter mutation (designated C) just after homeodomain, have been reported to cause atrial septal defect with atrial ventricular block. We here examined the functions of these three mutants of Csx/Nkx-2.5. The atrial natriuretic peptide (ANP) promoter was activated by wild type Csx/Nkx-2.5 (WT, approximately 8-fold), B ( approximately 2-fold), and C ( approximately 6-fold) but not by A. When A, B, or C was cotransfected into COS-7 cells with the same amount of WT, WT-induced activation of the ANP promoter was attenuated by A and B (A > B), whereas C further enhanced the activation. Immunocytochemical analysis using anti-Myc tag antibody indicated that transfected Myc-tagged WT, B, and C were localized in the nucleus of both COS-7 cells and cardiomyocytes of neonatal rats, whereas A was distributed diffusely in the cytoplasm and nucleus in COS-7 cells. Electrophoretic mobility shift assay showed that Csx/Nkx-2.5-binding sequences were bound strongly by WT and C, weakly by B, but not by A. Immunoprecipitation and GST pull-down assay revealed that WT and all mutants interacted with GATA-4. The synergistic activation of the ANP promoter by WT and GATA-4 was further enhanced by C but was inhibited by A and B. In the cultured cardiomyocytes, overexpression of C but not WT, A, or B, induced apoptosis. These results suggest that although the three mutants induce the same cardiac phenotype, transactivation ability and DNA binding ability are different among the three mutants and that apoptosis may be a cause for C-induced cardiac defect.

Animals↗
PubMed2000

beta-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes.

Apoptosis of cardiac myocytes is one of the causes of heart failure. Here we examine the mechanism by which the activation of beta-adrenergic receptor induces cardiomyocyte apoptosis. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling and DNA ladder analyses revealed that isoproterenol (Iso) induced the apoptosis of cardiac myocytes of neonatal rats through an increase in intracellular Ca(2+) levels. The Iso-induced cardiomyocyte apoptosis was strongly inhibited by the L-type Ca(2+) channel antagonist nifedipine and by the calcineurin inhibitors cyclosporin A and FK506. Iso reduced the phosphorylation levels of the proapoptotic Bcl-2 family protein Bad and induced cytochrome c release from mitochondria to the cytosol through calcineurin activation. Infusion of Iso increased calcineurin activity by approximately 3-fold in the hearts of wild-type mice but not in the hearts of transgenic mice that overexpress dominant negative mutants of calcineurin. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling analysis revealed that infusion of Iso induced apoptosis of cardiac myocytes and that the number of apoptotic cardiomyocytes was significantly less in the hearts of the transgenic mice compared with the wild-type mice. These results suggest that calcineurin plays a critical role in Iso-induced apoptosis of cardiac myocytes, possibly through dephosphorylating Bad.

Animals↗
PubMed2000

Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer.

Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer. Its oncogenic potential appears to depend on the state of tyrosine phosphorylation. However, the mechanisms by which ErbB-2 is constitutively tyrosine-phosphorylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL-treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension.

BACKGROUND: It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet. METHODS AND RESULTS: In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment. CONCLUSIONS: These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Animals↗
PubMed2000

Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products.

Interaction of advanced glycation end products (AGE) with AGE receptors induces several cellular phenomena potentially relating to diabetic complications. Five AGE receptors identified so far are RAGE (receptor for AGE), galectin-3, 80K-H, OST-48, and SRA (macrophage scavenger receptor class A types I and II). Since SRA is known to belong to the class A scavenger receptor family, and the scavenger receptor collectively represents a family of multiligand lipoprotein receptors, it is possible that CD36, although belonging to the class B scavenger receptor family, can recognize AGE proteins as ligands. This was tested at the cellular level in this study using Chinese hamster ovary (CHO) cells overexpressing human CD36 (CD36-CHO cells). Cellular expression of CD36 was confirmed by immunoblotting and immunofluorescent microscopy using anti-CD36 antibody. Upon incubation at 37 degrees C, (125)I-AGE-bovine serum albumin (AGE-BSA) and (125)I-oxidized low density lipoprotein (LDL), an authentic ligand for CD36, were endocytosed in a dose-dependent fashion and underwent lysosomal degradation by CD36-CHO cells, but not wild-type CHO cells. In binding experiments at 4 degrees C, (125)I-AGE-BSA exhibited specific and saturable binding to CD36-CHO cells (K(d) = 5.6 microg/ml). The endocytic uptake of (125)I-AGE-BSA by these cells was inhibited by 50% by oxidized LDL and by 60% by FA6-152, an anti-CD36 antibody inhibiting cellular binding of oxidized LDL. Our results indicate that CD36 expressed by these cells mediates the endocytic uptake and subsequent intracellular degradation of AGE proteins. Since CD36 is one of the major oxidized LDL receptors and is up-regulated in macrophage- and smooth muscle cell-derived foam cells in human atherosclerotic lesions, these results suggest that, like oxidized LDL, AGE proteins generated in situ are recognized by CD36, which might contribute to the pathogenesis of diabetic macrovascular complications.

Animals↗
PubMed2000

Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level.

In vivo studies suggest that sterol regulatory element-binding protein (SREBP)-1 plays a key role in the up-regulation of lipogenic genes in the livers of animals that have consumed excess amounts of carbohydrates. In light of this, we sought to use an established mouse hepatocyte cell line, H2-35, to further define the mechanism by which glucose regulates nuclear SREBP-1 levels. First, we show that these cells transcribe high levels of SREBP-1c that are increased 4-fold upon differentiation from a prehepatocyte to a hepatocyte phenotype, making them an ideal cell culture model for the study of SREBP-1c induction. Second, we demonstrate that the presence of precursor and mature forms of SREBP-1 protein are positively regulated by medium glucose concentrations ranging from 5. 5 to 25 mm and are also regulated by insulin, with the amount of insulin in the fetal bovine serum being sufficient for maximal stimulation of SREBP-1 expression. Third, we show that the increase in SREBP-1 protein is due to an increase in SREBP-1 mRNA. Reporter gene analysis of the SREBP-1c promoter demonstrated a glucose-dependent induction of transcription. In contrast, expression of a fixed amount of the precursor form of SREBP-1c protein showed that glucose does not influence its cleavage. Fourth, we demonstrate that the glucose induction of SREBP could not be reproduced by fructose, xylose, or galactose nor by glucose analogs 2-deoxy glucose and 3-O-methyl glucopyranose. These data provide strong evidence for the induction of SREBP-1c mRNA by glucose leading to increased mature protein in the nucleus, thus providing a potential mechanism for the up-regulation of lipogenic genes by glucose in vivo.

Animals↗
PubMed2000

Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. The smooth muscle myosin heavy chain study.

BACKGROUND: A rapid 30-minute assay of circulating smooth-muscle myosin heavy-chain protein has been developed as a biochemical diagnostic tool for aortic dissection. OBJECTIVE: To determine the sensitivity and specificity of this assay. DESIGN: Cross-sectional study. SETTING: 8 major cardiovascular centers in Japan. PATIENTS: 95 patients with acute aortic dissection, 48 patients with acute myocardial infarction, and 131 healthy volunteers. MEASUREMENTS: Levels of circulating smooth-muscle myosin heavy-chain protein. RESULTS: Patients with acute aortic dissection who presented within 3 hours after onset had elevated levels of circulating smooth-muscle myosin heavy-chain protein. In these patients, the assay had a sensitivity of 90.9%, a specificity of 98% compared with healthy volunteers, and a specificity of 83% compared with patients who had acute myocardial infarction; the clinical decision limit was 2.5 microgram/L. All patients with proximal lesions had elevated levels of smooth-muscle myosin heavy-chain protein, and only patients with distal lesions had decreased levels (<2.5 microgram/L). CONCLUSIONS: Levels of smooth-muscle myosin heavy-chain protein can be used to diagnose aortic dissection soon after symptom onset. The assay had the greatest diagnostic value in patients with proximal lesions.

Aged↗