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Biomedical subjects

Isao Kubota

Publications and source records attributed to Isao Kubota.

At least 19 recordsLinked to original sources
PubMed2004

Chronic hypertriglyceridemia in young watanabe heritable hyperlipidemic rabbits impairs endothelial and medial smooth muscle function.

Several studies have suggested that hypertriglyceridemia is a common risk factor for coronary heart disease. Although increasing serum levels of triglyceride correlate with hypercoagulability, little is known about the contribution of hypertriglyceridemia to vascular function. We successfully segregated two lines of rabbits with genetically-determined severely high (TGH; 2764 +/- 413 mg/dl) and moderately high (TGL; 191 +/- 12 mg/dl) levels of triglyceride, but with comparable levels of total cholesterol, from Watanabe heritable hyperlipidemic rabbits. To determine whether hypertriglyceridemia was involved in alterations of vascular function, we conducted isometric tension studies and analyzed protein expression on thoracic aortic rings isolated from young (3-4 month) TGH, TGL and Japanese White rabbit (JW). No difference in percentage of plaque area in the thoracic aorta was found between TGH and TGL. Relaxing responses, evoked by sodium nitroprusside were similar in JW, TGL and TGH, but endothelium-dependent relaxation to acetylcholine was impaired in TGH compared with JW or TGL (maximal relaxation in JW; 83.5 +/- 2.7%, TGL; 79.9 +/- 5.3%, TGH; 59.1 +/- 5.7%, p<0.05). Relaxation to A23187 was also attenuated in TGH compared with JW, but not significantly different between TGL and JW. Endothelium-independent relaxation elicited by isoproterenol in TGH was significantly decreased compared with JW or TGL (maximal relaxation in JW; 95.2 +/- 2.6% TGL; 91.0 +/- 4.9%, TGH; 75.1 +/- 5.2%, p<0.05). Protein expression of angiotensin II type-1 receptor was increased in TGH and that of nitric oxide synthases-3 was attenuated in TGH compared with TGL. This is the first study showing that endothelium-dependent and -independent vascular relaxation under the condition of combined hyperlipidemia was severely impaired as compared to that under only hypercholesterolemia. These results suggest that hypertriglyceridemia aggravates functional impairment induced by hypercholesterolemia in endothelial and smooth muscle cells.

Animals↗
PubMed2003

Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction.

BACKGROUND: Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and transduce similar signals as interleukin-1 receptor in response to exogenous pathogens. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, that may contribute to ventricular remodeling after myocardial infarction. In this study, we determined whether TLR-2 was involved in cardiac remodeling after myocardial infarction. METHODS AND RESULTS: Myocardial infarction was induced by surgical left anterior descending coronary artery ligation on wild-type (WT) mice and TLR-2-knockout (KO) mice. The survival rate was significantly higher in KO mice than in WT mice 4 weeks after myocardial infarction (65% versus 43%, P<0.03). Infarct size and degree of inflammatory cell infiltration in infarct area were similar between WT and KO mice. However, myocardial fibrosis in the noninfarct area of KO mice was much less than in WT mice (P<0.01) and was accompanied by reduced transforming growth factor-beta1 and collagen type 1 mRNA expressions (P<0.01 and P<0.05, respectively). Left ventricular dimensions at end diastole were smaller in KO mice than in WT mice at 1 week (P<0.05) and 4 weeks (P<0.01) after surgery. Furthermore, fractional shortening was higher (27.7+/-2.5% versus 21.2+/-2.6%, P<0.05, at 1 week, and 24.3+/-2.0% versus 16.6+/-2.5%, P<0.01, at 4 weeks) in KO mice compared with WT mice. CONCLUSIONS: These data suggest that TLR-2 plays an important role in ventricular remodeling after myocardial infarction.

Animals↗
PubMed2003

Role of thymidine phosphorylase on invasiveness and metastasis in lung adenocarcinoma.

Thymidine phosphorylase (TP) is expressed at higher levels in a variety of human cancers than in adjacent normal tissue. It is reported that the higher expression is associated with an increase of intratumoral microvessel density and a poor prognosis. We investigated the role of TP in human non small cell lung cancers (NSCLCs). The concentrations of TP in the tumors and the adjacent normal tissue from surgically resected specimens of 54 cases of NSCLCs were measured by using an enzyme-linked immunosorbent assay. Tumor specimens were also examined immunohistochemically. TP concentrations in the tumors were 169 +/- 18 units/mg protein (mean +/- SD), whereas those in normal tissue were 43 +/- 4 units/mg protein (mean +/- SD), consistent with TP staining patterns. There was no correlation between TP expression and microvessel density. Among clinicopathologic factors examined, the concentrations of TP but not TP immunoreactivity correlated with tumor differentiation in lung adenocarcinoma. Although a specific TP inhibitor (TPI) and overexpression of TP did not affect the growth of A549 lung adenocarcinoma cells, Matrigel invasion assay showed that A549 transfected with TP had higher invasive potential than mock transfectant, and such enhanced invasive activity was markedly diminished by treatment with TPI. Furthermore, administration of TPI suppressed lung metastasis of TP-overexpressing A549 cells in nude mice. These results demonstrate that TP may play an important role in tumor differentiation, invasiveness and metastasis in lung adenocarcinoma, and suggest that TP could be a novel target for treatment of TP-overexpressing lung adenocarcinoma.

Aged↗
PubMed2003

Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium.

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca2+ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca2+ ions and a small increase in Ca2+ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKCepsilon from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na+-H+ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pHi did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca2+ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.

Animals↗
PubMed2003

Enhanced regional washout of technetium-99m-sestamibi in patients with coronary spastic angina.

BACKGROUND: Reverse redistribution and rapid washout of 99mTc-sestamibi are observed in patients with acute myocardial infarction and may indicate viable myocardium. However, the clinical significance of this phenomenon has not been rigorously examined in other cardiac diseases. Thus, we investigated whether reverse redistribution and washout of 99mTc-sestamibi could be used in the diagnosis and follow-up of patients with coronary spastic angina. METHODS: Thirty patients diagnosed as coronary spastic angina were examined. During coronary arteriography, spasm was induced by provocation test with ergonovine, and only total or subtotal occlusion was considered positive. Myocardial perfusion tomography was obtained 45 min (early) and 3 hr (delayed) after 99mTc-sestamibi injection. Segmental defect score was visually graded from 0 (normal) to 4 (defect), and a total defect score was determined as the sum of defect scores for all segments. Washout rate of 99mTc-sestamibi from the myocardium was calculated for each segment. After medical treatment with calcium antagonists and nitrates for 3 months, 99mTc-sestamibi imaging was repeated. RESULTS: Out of 30 patients, on the early images 17 (57%) patients demonstrated decreased 99mTc-sestamibi uptake in spastic segments; on the other hand, 24 (80%) patients did decreased 99mTc-sestamibi uptake in spastic segments on delayed images. Total defect scores in delayed images were higher than those in early images (6.9 +/- 0.3 vs. 3.6 +/- 0.4, p < 0.01). Reverse redistribution of 99mTc-sestamibi was observed in 17 out of 30 patients (57%) with coronary spastic angina. Washout rate of 99mTc-sestamibi from spastic segments was higher than that from non-spastic segments (16 +/- 2% vs. 11 +/- 5%, p < 0.01). After medical treatment, washout rate from spastic segments was decreased to 10 +/- 4 (p < 0.01), and left ventricular ejection fraction was increased from 63 +/- 8% to 73 +/- 4% (p < 0.01). CONCLUSION: Rapid washout of 99mTc-sestamibi was observed in patients with coronary spastic angina and might indicate that the ability of myocyte to retain the tracer was impaired due to repetitive brief ischemia by coronary spasm. The early and delayed 99mTc-sestamibi imaging provides useful information for the diagnosis and responses to the treatment in patients with coronary spastic angina.

Adult↗
PubMed2003

Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes.

OBJECTIVE: Fas ligand (FasL) is a key cytokine which initiates apoptosis when FasL binds to its receptor, Fas. Cardiac myocytes are generally resistant to Fas-induced apoptosis. However, sublethal dose of doxorubicin (Dox) can sensitize cardiac myocytes to Fas-induced apoptosis. We investigated the molecular mechanism by which Dox sensitizes cardiac myocytes to Fas-induced apoptosis. FLICE inhibitory protein (FLIP) is a key molecule for blocking Fas-induced apoptosis by functioning as a caspase-8 dominant negative. METHODS AND RESULTS: FLIP was constitutively expressed in cultured neonatal rat cardiac myocytes. FLIP protein levels were markedly down-regulated by Dox in a time-dependent and dose-dependent manner. Next, we examined the relation of reactive oxygen species (ROS) by Dox to the expression of FLIP. Both of N-acetylcysteine (NAC) and the combination of superoxide dismutase and catalase restored the decreased FLIP in Dox-treated cardiac myocytes to the basal level. NAC also restored the increased formation of thiobarbituric acid-reactive substance after Dox-treatment. Concurrently, the susceptibility to Fas-mediated apoptosis disappeared with the treatments of the antioxidant agents. Hydrogen peroxide down-regulated FLIP in a dose-dependent fashion and also sensitized cardiac myocytes to Fas-induced apoptosis. CONCLUSIONS: FLIP, an inhibitor of apoptosis induced by cytokines of TNF family, contributes at least partly to Dox-induced sensitization to Fas-mediated apoptosis in cardiac myocytes. The expression of FLIP in cardiac myocytes is regulated by ROS.

Acetylcysteine↗
PubMed2003

Low-dose flecainide infusion followed by oral pilsicainide is highly effective and safe for paroxysmal atrial fibrillation.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of intravenous infusion of low-dose flecainide (50 mg) followed by oral pilsicainide (50 mg t.i.d.)in patients with paroxysmal atrial fibrillation (AF). METHODS: Thirty-one patients with symptomatic and hemodynamically stable AF lasting less than 48 h from its onset were enrolled. Firstly, intravenous flecainide was given, and if AF was maintained 1 h after the start of flecainide, oral pilsicainide was started. RESULTS: Sinus rhythm was restored in 14 patients by flecainide alone (45%), and 24 h later, AF was disappeared in additional 14 patients (45%), resulting in the overall conversion rate of 90%. No side effects were observed. CONCLUSIONS: The combined therapy of i.v. low-dose flecainide followed by oral pilsicainide might be a promising strategy for the outpatient treatment of paroxysmal atrial fibrillation.

Anti-Arrhythmia Agents↗
PubMed2003

Antineutrophil cytoplasmic antibody positive alveolar haemorrhage during propylthiouracil therapy for hyperthyroidism.

Recently, propylthiouracil (PTU) has been thought to be one of the possible causes of antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis syndrome, resulting in glomerulonephritis and, infrequently, diffuse alveolar haemorrhage (DAH). The mechanism of ANCA-positive vasculitis during PTU therapy is still unknown. Herein, we describe the case of a 59-year-old woman who developed myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA positive DAH, without any other organ system involvement, during PTU therapy. Diminution and discontinuation of PTU resulted in a positive response. To our knowledge, this is the first documentation of both MPO- and PR3-ANCA-positive DAH, without systemic manifestations, developing during PTU therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2003

Severity in myocardial dysfunction contributed to long-term fluctuation of heart rate, rather than short-term fluctuations.

BACKGROUND: It is known that heart rate shows complex behavior, long-term fluctuation of heart rate, and short-term fluctuations in heart failure. Analyzing these properties and examining the relationship to the disease, severity may increase the understanding of the background of heart rate variability (HRV). METHODS: In 61 patients (mean age 65 +/- 9 years, 32 ischemic heart disease, 29 cardiomyopathy), with myocardial dysfunction, 24-hour ambulatory electrocardiography was performed. After the construction of the time series of R-R intervals, 15 HRV parameters were measured, including mean heart rate, standard deviation of N-N intervals (SDNN), ratio of low frequency/high frequency power (LF/HF), HRV triangular index (TI), and ratio of length/width at the 90% level of all scattered points. RESULTS: By using the multiple regression analysis, we tested which HRV parameter (HR, SDNN, LF/HF, TI, or length/width) independently correlated with left ventricular ejection fraction (EF) or left ventricular diastolic dimension (EDD). The results demonstrated that TI and SDNN independently correlated with EF (multiple R = 0.59). Moreover, TI and SDNN independently correlated with EDD (multiple R = 0.45). CONCLUSION: TI and SDNN were indicators of the disease severity in myocardial dysfunction, while LF/HF, indicators of autonomic tone, did not have such an ability. It was of interest that the disease severity contributed to long-term fluctuations (TI, SDNN) of heart rate, rather than short-term fluctuations (LF/HF).

Aged↗
PubMed2003

Dual response to Fas ligation in human endothelial cells: apoptosis and induction of chemokines, interleukin-8 and monocyte chemoattractant protein-1.

BACKGROUND: To maintain the integrity of tissues, endothelial cells play critical roles. Fas ligand (FasL) is well known to deliver a death signal through its receptor, Fas. The Fas/FasL system may concomitantly induce expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) besides triggering apoptosis in endothelial cells. We also investigated whether an inhibitor of caspase-8 (Z-IETD-FMK) does modulate IL-8 and MCP-1 secretion. METHODS AND RESULTS: After treatment with interferon-gamma (IFN-gamma), human recombinant FasL (hr FasL) or Fas agonistic antibody (CH-11) was added to cultured human endothelial cells. IFN-gamma up-regulated Fas mRNA levels. Fas ligation promoted apoptosis assessed by fluorescent-activated cell sorter (FACS) analysis in a dose-dependent manner and induced prominent DNA fragmentation. Simultaneously, IL-8 and MCP-1 were secreted from the endothelial cells in response to hr FasL or CH-11 in a dose-dependent manner (P < 0.01). Fas-neutralizing agent (Fas-Fc) suppressed the Fas-mediated secretions of IL-8 and MCP-1 (P < 0.01) both as well as the Fas-mediated apoptosis. On the other hand, whereas Z-IETD-FMK suppressed apoptosis, the inhibitor enhanced the Fas-mediated secretions of both IL-8 and MCP-1 beyond the value of the Fas stimulation alone (P < 0.01), suggesting an enhanced signalling for the chemokine expression. CONCLUSION: In human endothelial cells, the Fas/FasL system induces both IL-8 and MCP-1 secretions probably via a caspase-8 independent pathway. The Fas/FasL system may amplify the inflammatory cascade in the vascular injury and atherogenesis by recruiting leukocytes at the region of apoptotic endothelial damage.

Apoptosis↗
PubMed2003

Improvement of ventricular arrhythmia by octreotide treatment in acromegalic cardiomyopathy.

We report a case of acromegalic cardiomyopathy in a 46-year-old Japanese man with pituitary adenoma. Increased secretion of growth hormone and insulin-like growth factor I were detected. He had left ventricular hypertrophy, impaired cardiac function, and frequent ventricular premature complexes. After 2-month treatment with octreotide, a long-acting somatostatin analogue, levels of both hormones were decreased. At the same time, left ventricular hypertrophy (intraventricular septal thickness: 22.5 to 17.8 mm), cardiac function (ejection fraction: 38 to 50%), and frequency of ventricular premature complexes (17,249 to 2,882 beats a day) were improved. Transsphenoidal surgery was then safely performed. Treatment with octreotide is thought to have some effect on improvement of ventricular arrhythmia in acromegalic heart.

Acromegaly↗
PubMed2003

Role of nitric oxide in the progression of cardiovascular remodeling induced by carotid arterio-venous shunt in rabbits.

Despite a variety of biological roles for nitric oxide (NO) in the cardiovascular system, little is known about whether NO is involved in cardiac hypertrophy. We hypothesized that NO production following a sustained increase in shear stress by volume-overload modifies the level of cardiac hypertrophy independent of hemodynamic changes. Volume-overload was induced by shunt formation between the left common carotid artery and the external jugular vein in 21 rabbits. These shunt rabbits were randomly assigned to 3 groups: shunt with no treatment (n = 8), shunt treated with a low dose of N(G)-nitro-L-arginine methyl ester (L-NAME. 0.5 g/L in drinking water, n=8), and shunt with a high dose of L-NAME (1.5 g/L, n = 5). Eight sham operated rabbits were used as controls. Treatments were started immediately after operation and were continued for 6 weeks. Chronic volume-overload by shunt formation caused left ventricular dilatation and arterial enlargement proximal to the fistula. The relative wall thickness of the left ventricle was decreased, indicating eccentric cardiac hypertrophy. L-NAME elevated mean arterial blood pressure (P < 0.01) and reduced the increment of cardiac output (P < 0.05). L-NAME attenuated ventricular weight (P < 0.01) ventricular cavity dilatation (P < 0.01). and arterial enlargement (P < 0.05). The re-capitulation of atrial natriuretic factor mRNA in the hypertrophied left ventricular myocardium by volume-overload was attenuated with L-NAME. In this model with chronic volume-overload, NO plays a pivotal role in the progression of cardiovascular remodeling by regulating the loading conditions of the heart.

Animals↗
PubMed2003

Direct evidence that sustained dysfunction of left atrial appendage contributes to the occurrence of cardiogenic brain embolism in patients with paroxysmal atrial fibrillation.

OBJECTIVE: The goal of this study was to investigate transesophageal echocardiographic (TEE) findings after the termination of atrial fibrillation to clarify the direct evidence for occurrence of acute cardiogenic brain embolism (CBE) in patients with paroxysmal atrial fibrillation (PAF). PATIENTS AND METHODS: Among 98 consecutive patients with CBE, we investigated TEE in 16 patients with PAF (Group CBE, 72 +/- 10 years) within 7 days of the onset and 2 weeks after the first study, in comparison with 15 age-matched PAF patients without CBE (Group N). The duration from reversal to normal sinus rhythm to first TEE was 6 +/- 1 days in both groups. RESULTS: There were no significant differences in left atrial dimension and emptying flow velocity of the left atrial appendage (LAA-eV) between groups. Group CBE had significantly larger LAA area (4.3 +/- 1.3 cm2 vs. 3.1 +/- 1.0 cm2, p < 0.05), smaller LAA fractional area change (LAA-FAC) (43 +/- 25% vs. 80 +/- 22%, p < 0.001), and a higher incidence of left atrial spontaneous echo contrast (LAA-SEC) (25% vs. 7%, p < 0.05) than group N, and those abnormalities in group CBE were significantly improved at the second TEE (LAA area: to 3.2 +/- 0.9 cm2, p < 0.05; LAA-FAC: to 84 +/- 26%, p < 0.001; LAA-SEC: to 0%, p < 0.05), respectively. CONCLUSION: LAA-FAC is a more sensitive marker for LAA dysfunction than the widely used index, LAA-eV, and a sustained deterioration of LAA-FAC may be direct evidence for thrombus formation and occurrence of acute CBE in patients with PAF.

Aged↗
PubMed2003

Renal cholesterol embolic disease effectively treated with steroid pulse therapy.

A 65-year-old man developed acute renal failure with eosinophilia two weeks after a coronary bypass operation and angiography. Renal biopsy revealed cholesterol crystal embolism (CCE) in glomeruli and arterioles. Low-dose corticosteroid therapy failed to recover the renal function; further deterioration of renal function and peripheral ischemic symptoms such as livedo reticularis and blue toes occurred. However, steroid pulse therapy successfully attenuated CCE-induced renal failure and eosinophilia. It is suggested that steroid pulse therapy might be effective to treat CCE-induced renal failure and eosinophilia could be a useful marker for activity of CCE.

Aged↗
PubMed2003

Fibrillary glomerulonephritis with hypocomplementemia.

A 59-year-old man was referred for evaluation of nephrotic syndrome. The patient was diagnosed to have rheumatoid arthritis and had been treated for 10 years. Renal biopsy showed mesangial proliferation with small nodular formations, which were determined as fibrillary deposits (average diameter: 20 nm) by electromicroscopy. Congo-red stain was negative. The laboratory findings revealed hypocomplementemia and lambda type of Bence-Jones protein in urine without other systemic diseases including multiple myeloma. Immunosuppressive therapy did not attenuate the nephrotic-range proteinuria. Such a case of fibrillary glomerulonephritis with hypocomplementemia is rare.

Anti-Inflammatory Agents↗
PubMed2003

In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)I-metaiodobenzylguanidine.

UNLABELLED: Scintigraphic evaluation of (123)I-metaiodobenzylguanidine ((123)I-MIBG) in the lungs is considered to recognize endothelial cell lesions. The aim of this study was to clarify the involvement of the pulmonary microvascular injury in the pathogenesis of chronic obstructive pulmonary disease (COPD). METHODS: We investigated lung (123)I-MIBG kinetics and clinical indices in 25 COPD patients and 12 control subjects. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planer images at 30 min (early image) and 270 min (delayed image) after intravenous injection of (123)I-MIBG. Pulmonary mean washout rate (WR) of the (123)I-MIBG was also calculated. RESULTS: The L/M ratios in both early and delayed images of COPD patients, as well as its WR, were significantly lower than those of the control subjects (L/M early: 1.26 +/- 0.18 vs. 1.54 +/- 0.11, P < 0.0001; L/M delayed: 1.20 +/- 0.12 vs. 1.33 +/- 0.09, P < 0.001; WR: 27.4% +/- 5.3% vs. 34.2% +/- 5.7%, P < 0.01). There were significant relationships between lung WR of the (123)I-MIBG and other diagnostic tests for the severity of COPD, such as forced expiratory volume in 1 s (% FEV(1.0): r = 0.386, P < 0.05), carbon monoxide diffusing capacity/alveolar volume (DL(CO)/V(A): r = 0.449, P < 0.01), arterial blood oxygen pressure (PaO(2): r = 0.474, P < 0.01), alveolar-arterial oxygen tension gradient [A-a]DO(2) (r = -0.446, P < 0.01), and percentage of low-attenuation area (r = -0.458, P < 0.01) in the study population. CONCLUSION: Because lung WR of the (123)I-MIBG is considered to be independent of an alteration of the pulmonary vascular surface area, these results suggest that the microvascular endothelial cell injury plays a significant role in the pathogenesis of COPD.

3-Iodobenzylguanidine↗