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Biomedical subjects

Ryozo Nagai

Publications and source records attributed to Ryozo Nagai.

At least 37 records · Page 2Linked to original sources
PubMed2006

Myocardial glucose utilisation in type II diabetes mellitus patients treated with sulphonylurea drugs.

PURPOSE: Chronic sulphonylurea treatment maintains improved glycaemic control through mechanisms other than enhancement of insulin secretion and may act on various organs. The aim of this study was to investigate whether the chronic use of sulphonylurea drugs influences PET measurement of myocardial glucose utilisation (MGU) in type II diabetes mellitus. METHODS: Forty-two patients with type II diabetes mellitus and 17 control subjects underwent dynamic (18)F-FDG PET to measure MGU during hyperinsulinaemic euglycaemic clamping. Twenty-one patients had been taking sulphonylurea drugs for more than 1 year (SU group), and the other 21 patients were drug naive (non-SU group). The haemoglobin A1c levels in the two patient groups were similar. Glucose disposal rate (GDR) was also determined as a marker of whole-body insulin resistance. RESULTS: GDR in the SU group (9.01+/-2.53 mg min(-1) kg(-1)) was significantly higher than that in the non-SU group (4.10+/-2.47, p<0.01) and was similar to that in the controls (9.76+/-2.97). MGU in the SU group (7.66+/-3.02 mg min(-1) 100 g(-1)) was significantly higher than that in the non-SU group (5.53+/-2.05, p<0.01) and was similar to that in the controls (7.49+/-2.74). CONCLUSION: Chronic sulphonylurea treatment influences MGU independent of the degree of glycaemic control. The effect of medication should be kept in mind when measuring and interpreting MGU in patients with type II diabetes mellitus.

Diabetes Mellitus, Type 2↗
PubMed2006

Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6.

BACKGROUND: Macrophage scavenger receptors facilitate the uptake of modified low-density lipoprotein (LDL), formation of foam cells, and development of atherosclerosis. Given that proinflammatory cytokines, including IL-6, can modulate the macrophage foaming process, the aim of the present study was to determine whether the synthetic retinoic acid receptor-alpha/beta-specific agonist Am80, which is also an IL-6 inhibitor, can modulate macrophage lipid accumulation and foam cell formation. METHODS AND RESULTS: Am80 suppressed IL-6 production induced by 12-myristate 13-acetate (PMA) or angiotensin II in mouse Raw264 macrophages. It also suppressed expression of the 2 major scavenger receptors (scavenger receptor-A [SR-A] and CD36), in part by inhibiting IL-6, and inhibited macrophage foam cell formation. Systemic administration of Am80 led to reductions in the areas of atherosclerotic lesions and foam cell accumulation in the aortas of apolipoprotein E (apoE)-deficient mice and reduced serum concentrations of IL-6 and IL-1beta without affecting body weights, serum lipid profiles or IL-10 levels. CONCLUSIONS: Am80 suppresses scavenger receptor expression and macrophage foam cell formation in vitro and prevents atherogenesis in apoE-deficient mice in vivo. This suggests Am80 is a novel candidate agent that could be highly useful in the prevention and treatment of atherosclerosis.

Animals↗
PubMed2006

Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways.

Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.

Adiponectin↗
PubMed2006

New insights in the treatment strategy for pulmonary arterial hypertension.

INTRODUCTION: Recent advances in our understanding of the pathophysiological and molecular mechanisms involved in pulmonary arterial hypertension have led to the development of novel and rational pharmacological therapies. In addition to conventional therapy (i.e., supplemental oxygen and calcium channel blockers), prostacyclin or endothelin receptor antagonists have been recommended as a first-line therapy for pulmonary arterial hypertension. However, these treatments have potential limitations with regard to their long-term efficacy and improvement in survival. Furthermore, intravenous prostacyclin (epoprostenol) therapy, which is recommended by most experts for patients with New York Heart Association (NYHA) functional class IV, is complicated, uncomfortable for patients, and expensive because of the cumbersome administration system. Considering these circumstances, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease. CASE REPORT: In this short review, we present an overview of the current treatment options for pulmonary arterial hypertension and describe a case report with primary pulmonary hypertension. A male patient with NYHA functional class IV and showing no response to calcium channel blockers and prostacyclin exhibited significantly improved exercise tolerance and hemodynamics and long-term survival for more than 2.5 years after receiving an oral combination therapy of a phosphodiesterase type 5 inhibitor (sildenafil), phosphodiesterase type 3 inhibitor (pimobendan), and nicorandil. FUTURE PERSPECTIVE: We also discuss the background and plausible potential mechanisms involved in this case, as well as future perspectives in the treatment of pulmonary arterial hypertension.

Anticoagulants↗
PubMed2006

DeltaEF1 mediates TGF-beta signaling in vascular smooth muscle cell differentiation.

Alteration in the differentiated state of smooth muscle cells (SMCs) is known to be integral to vascular development and the pathogenesis of vascular disease. However, it is still largely unknown how environmental cues translate into transcriptional control of SMC genes. We found that deltaEF1 is upregulated during SMC differentiation and selectively transactivates the promoters of SMC differentiation marker genes, SM alpha-actin and SM myosin heavy chain (SM-MHC). DeltaEF1 physically interacts with SRF and Smad3, resulting in a synergistic activation of SM alpha-actin promoter. Chromatin immunoprecipitation assays and knockdown experiments showed that deltaEF1 is involved in the control of the SMC differentiation programs induced by TGF-beta signaling. Overexpression of deltaEF1 inhibited neointima formation and promoted SMC differentiation, whereas heterozygous deltaEF1 knockout mice exhibited exaggerated neointima formation. It thus appears deltaEF1 mediates SMC differentiation via interaction with SRF and Smad3 during development and in vascular disease.

Actins↗
PubMed2006

Effects of adrenomedullin on acute ischaemia-induced collateral development and mobilization of bone-marrow-derived cells.

Adrenomedullin exerts not only vasodilatory effects, but also angiogenic effects. In the present study, we investigated the effects of adrenomedullin on collateral formation and circulating bone-marrow-derived cells after acute tissue ischaemia. Bone marrow of 8-10-week-old female C57BL/6J mice was replaced with that from GFP (green fluorescent protein) transgenic mice (GFP mice). At 8 weeks after transplantation, hindlimb ischaemia was induced by resecting the right femoral artery and a plasmid expressing human adrenomedullin (50 mug) was injected into the ischaemic muscle, followed by in vivo electroporation on a weekly basis. Overexpression of adrenomedullin significantly enhanced the blood flow recovery compared with controls (blood flow ratio, 1.0+/-0.2 compared with 0.6+/-0.3 respectively, at week 4; P<0.05) and increased capillary density in the ischaemic leg as determined by anti-CD31 immunostaining of the ischaemic muscle (567+/-40 compared with 338+/-65 capillaries/mm(2) respectively, at week 5; P<0.05). There were more GFP-positive cells in the thigh muscle of the mice injected with adrenomedullin than in that of the control mice (29.6+/-4.5 compared with 16.5+/-3.3 capillaries/mm(2) respectively, at week 5; P<0.05). We repeated the same experiments using LacZ-knock-in mice instead of GFP mice, and obtained similar results. These findings suggest that adrenomedullin may augment ischaemia-induced collateral formation with some effects on circulating bone-marrow-derived cells.

Adrenomedullin↗
PubMed2006

A case of cholesterol embolism confirmed by skin biopsy and successfully treated with statins and steroids.

Although cholesterol embolism syndrome was recognized as a clinicopathologic entity more than 50 years ago, it is attracting growing attention recently. It is a multisystemic disorder in which cholesterol crystals released from atherosclerotic plaques obstruct small arterioles, resulting in local ischemia and end-organ damage. There are no established treatments, and with the limited treatment options available, it is important to make the diagnosis as early as possible. We present the case of a 68-year-old man with cholesterol embolism who had a few fluttering atheromas in the aorta, as demonstrated by transesophageal ultrasonography. The diagnosis was confirmed by skin biopsy, and treatment with statins and steroids proved effective, as renal failure progressively improved. This case emphasizes the importance of early diagnosis and shows the possible therapeutic effects of statins and steroids for patients with this syndrome.

Aged↗
PubMed2006

Comparative effects of azelnidipine and other Ca2+-channel blockers on the induction of inducible nitric oxide synthase in vascular smooth muscle cells.

Overproduction of nitric oxide by inducible nitric oxide synthase contributes to the progression of cardiovascular disease. We investigated the effects of azelnidipine and other Ca2+-channel blockers on nitric oxide production by cultured aortic smooth muscle cells isolated from Wistar rats and human umbilical vein endothelial cells (HUVECs), using the Griess reaction and oxyhemoglobin method. Release of lactic dehydrogenase (LDH) was measured to evaluate cell damage, and immunohistochemistry was performed to examine the expression of inducible nitric oxide synthase and nitrotyrosine protein. Azelnidipine and other Ca2+-channel blockers inhibited the release of nitric oxide induced by lipopolysaccharide plus interferon-gamma. Azelnidipine inhibited it most potently among the Ca2+-channel blockers tested (azelnidipine, amlodipine, nifedipine, diltiazem, verapamil, and nicardipine) at a concentration of 10 microM. Longer stimulation with these agents induced the expression of inducible nitric oxide synthase and nitrotyrosine, with an increase of lactic dehydrogenase release, whereas azelnidipine suppressed these changes. In human umbilical vein endothelial cells, azelnidipine enhanced basal nitric oxide production by endothelial nitric oxide synthase. In conclusion, azelnidipine potently inhibited the induction of inducible nitric oxide synthase and then nitric oxide production in vascular smooth muscle cells, while enhancing constitutive nitric oxide production by endothelial cells. Azelnidipine may inhibit nitrotyrosine expression and cell damage caused by overproduction of nitric oxide, suggesting a mechanism for its cardiovascular protective effect.

Animals↗
PubMed2006

Upregulated neurohumoral factors are associated with left ventricular remodeling and poor prognosis in rats with monocrotaline-induced pulmonary arterial hypertension.

BACKGROUND: Left ventricular remodeling might be involved in the pathophysiology of right ventricular hypertrophy/failure due to pulmonary arterial hypertension (PAH), while the left ventricle is considered not under pressure/volume overload. METHODS AND RESULTS: Rats with monocrotaline-induced PAH were used in the present study to examine whether upregulated neurohumoral factors may induce left ventricular (LV) remodeling and(/or) contribute to prognosis. Morphological analysis revealed a significant increase in the weight of the free walls of both ventricles and the interventricular septum, indicating biventricular hypertrophy, although systemic blood pressure was not elevated. RNase protection assay demonstrated the activation of a fetal gene program in the cardiac muscle of the left and right ventricular free walls. Similar activation of the fetal gene program was observed in the LV of rats continuously infused with angiotensin (AT) II, although this was not the case for rats infused with isoproterenol. Measured plasma levels of ATII, noradrenaline, and brain natriuretic peptide (BNP) were all significantly elevated in the PAH rats. Furthermore, the plasma BNP level positively correlated with the ratio of heart weight to body weight and the plasma level of ATII. Not right but LV hypertrophy was significantly reduced by treatment with an AT II type 1 receptor blocker, valsartan, whereas the effect of an adrenergic alpha1 and beta1,2 blocker, carvedilol, was borderline. Survival rate in the PAH rats was significantly improved when they were treated with valsartan or carvedilol. CONCLUSIONS: Upregulated neurohumoral factors seem to play an important role in LV remodeling without mechanical overload, and are associated with impairment of prognosis in rats with PAH.

Angiotensin II↗
PubMed2006

Focalized contractile impairment at hypertrophied myocardium proven in consideration of wall stress in patients with hypertrophic cardiomyopathy.

In hypertrophic cardiomyopathy (HCM) a hyperkinetic state is sometimes observed in spite of impaired systolic function in the hypertrophied myocardium. The aim of the present study was to determine the mechanism of this paradox. Seventeen patients with HCM and 10 normal subjects underwent cine magnetic resonance (MR) imaging to measure percent systolic wall thickening and percent fractional shortening. The ratio of systolic radial wall stress of the LV at the hypertrophied myocardium over that at the nonhypertrophied myocardium was evaluated to describe the focal advantageous condition for wall thickening. The ratio was 0.66 +/- 0.36 at the start of contraction and 0.78 +/- 0.31 at early-systole, indicating consistently smaller radial wall stress at the hypertrophied myocardium. Although the condition for contraction was favorable (a ratio less than 1.00), percent systolic wall thickening at the hypertrophied myocardium (23.0 +/- 11.8%) was smaller than that at the nonhypertrophied myocardium (70.5 +/- 32.3%). Smaller end-diastolic dimension (HCM group; 45.2 +/- 4.2 mm, reference group; 48.9 +/- 4.1 mm, P = 0.04) with a statistically identical value of systolic decrease in intraventricular dimension (HCM group; 19.7 +/- 3.9 mm, reference group; 18.9 +/- 3.2 mm, P = 0.60) yielded high percent fractional shortening in patients with HCM (43.5 +/- 7.6%). Although contractile impairment was proven at the hypertrophied region with low radial wall stress in the HCM group, the smaller end-diastolic dimension in this group resulted in high percent fractional shortening.

Cardiomyopathy, Hypertrophic↗
PubMed2006

18F-fluorodeoxyglucose positron emission tomography in a case of retroperitoneal fibrosis.

A patient with recurrent abdominal pain was admitted to our hospital. Computed tomography showed a soft dense mass surrounding the abdominal aorta at the infrarenal level, which was compatible with retroperitoneal fibrosis. (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography showed abnormal uptake of (18)F-FDG into these lesions. Two months after the initiation of corticosteroid therapy, the abnormal uptake of (18)F-FDG had ceased along with a reduction in the fibrous mass surrounding the abdominal aorta.

Abdominal Pain↗
PubMed2006

Amiodarone and N-desethylamiodarone enhance endothelial nitric oxide production in human endothelial cells.

Amiodarone (AM) is a potent vasodilator and exhibits diverse cardiovascular protective effects in vivo, but their underlying mechanisms remain unsettled. We investigated the effects of AM and N-desethylamiodarone (DEA), the major metabolite of AM, on endothelial nitric oxide (NO) production using cultured human umbilical vein endothelial cells (HUVECs). The release of NO was evaluated as measured by nitrite, a stable metabolite of NO, using the Griess reaction and also measured directly by a NO-selective electrode. The expression of each nitric oxide synthase (NOS) mRNA was examined by reverse transcriptase-polymerase chain reaction (RT-PCR), and the effects of AM on eNOS mRNA expression were studied by quantitative real-time RT-PCR. AM and DEA (1-30 microM) enhanced NO production in a concentration-dependent manner. DEA was capable of producing more NO than AM. L-NAME, a nonselective NOS inhibitor, EGTA, a Ca(2+)-chelating agent, and nickel, a nonspecific Ca(2+) blocker, all inhibited AM-induced NO production. However, LY294002, an Akt pathway inhibitor and SB202190, a MAP kinase inhibitor, did not significantly suppress the production. In RT-PCR analysis, only eNOS mRNA was detected. Treatment with AM for 4 hours did not show a significant increase in the expression of eNOS mRNA. AM lower than 30 microM did not induce apoptosis, net cell loss, or LDH release from cells. The present study provides the first evidence that therapeutic concentrations of AM and DEA enhance eNOS-mediated NO production without any toxic or apoptotic effects. This mechanism may underlie the cardiovascular protective effects of AM and its metabolite observed in a clinical setting.

Amiodarone↗
PubMed2006

Identification of a novel member of the carboxylesterase family that hydrolyzes triacylglycerol: a potential role in adipocyte lipolysis.

Molecular mechanisms underlying lipolysis, as defined by mobilization of fatty acids from adipose tissue, are not fully understood. A database search for enzymes with alpha/beta hydrolase folds, the GXSXG motif for serine esterase and the His-Gly dipeptide motif, has provided a previously unannotated gene that is induced during 3T3-L1 adipocytic differentiation. Because of its remarkable structural resemblance to triacylglycerol hydrolase (TGH) with 70.4% identity, we have tentatively designated this enzyme as TGH-2 and the original TGH as TGH-1. TGH-2 is also similar to TGH-1 in terms of tissue distribution, subcellular localization, substrate specificity, and regulation. Both enzymes are predominantly expressed in liver, adipose tissue, and kidney. In adipocytes, they are localized in microsome and fatcake. Both enzymes hydrolyzed p-nitophenyl butyrate, triolein, and monoolein but not diolein, cholesteryl oleate, or phospholipids; hydrolysis of short-chain fatty acid ester was 30,000-fold more efficient than that of long-chain fatty acid triacylglycerol. Fasting increased the expression of both genes in white adipose tissue, whereas refeeding suppressed their expression. RNA silencing of TGH-2 reduced isoproterenol-stimulated glycerol release by 10% in 3T3-L1 adipocytes, while its overexpression increased the glycerol release by 20%. Thus, TGH-2 may make a contribution to adipocyte lipolysis during period of increased energy demand.

3T3 Cells↗
PubMed2006

Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

Chromosome Mapping↗
PubMed2006

Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome.

OBJECTIVE: The high-molecular weight (HMW) form of adiponectin, an adipocyte-derived insulin-sensitizing hormone, has been reported to be the most active form of this hormone. We investigated whether measurement of plasma HMW adiponectin levels, using our newly developed enzyme-linked immunosorbent assay system for selective measurement of human HMW adiponectin level, may be useful for the prediction of insulin resistance and metabolic syndrome. RESEARCH DESIGN AND METHODS: A total of 298 patients admitted for diabetes treatment or coronary angiography served as study subjects. Receiver operator characteristic (ROC) curves for the HMW ratio (HMWR; ratio of plasma level of HMW adiponectin to that of total adiponectin) and plasma total adiponectin levels were plotted to predict the presence of insulin resistance and metabolic syndrome. RESULTS: The area under the ROC curve (AUC) of the HMWR values to predict the presence of insulin resistance was significantly larger than that of plasma total adiponectin level in total subjects (0.713 [95% CI 0.620-0.805] vs. 0.615 [0.522-0.708], P = 0.0160). The AUC for the HMWR values to predict the presence of metabolic syndrome was significantly larger than that for plasma total adiponectin levels in men (0.806 [0.747-0.865] vs. 0.730 [0.660-0.800], P = 0.0025) and in women (0.743 [0.659-0.828] vs. 0.637 [0.532-0.742], P = 0.0458). CONCLUSIONS: The HMWR value has better predictive power for the prediction of insulin resistance and metabolic syndrome than plasma total adiponectin level.

Adiponectin↗
PubMed2006

A polymorphism in the AMPKalpha2 subunit gene is associated with insulin resistance and type 2 diabetes in the Japanese population.

AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the alpha2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5' and 3' flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P = 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P = 0.021; and 356 case and 192 control subjects from the same area in Japan, P = 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P = 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n = 272], P = 0.002; and joint replication control subjects [n = 552], P = 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population.

3' Untranslated Regions↗