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Biomedical subjects

Mitsuaki Isobe

Publications and source records attributed to Mitsuaki Isobe.

83 records · Page 5Linked to original sources
PubMed2002

ATF3 inhibits doxorubicin-induced apoptosis in cardiac myocytes: a novel cardioprotective role of ATF3.

Activating transcription factor (ATF) 3, a member of the ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors, is induced by a wide range of stress stimuli. Although the ATF3 homodimer is known to repress transcription of several genes, its precise biological roles are still unclear. In this study, we investigated the functional role of ATF3 in doxorubicin (DOX=adriamycin)-treated neonatal rat cardiac myocytes. DOX rapidly activated JNK and c-Jun and induced ATF3 at both mRNA and protein level. Adenovirus-mediated expression of ATF3 protected cardiomyocytes from DOX-induced apoptosis, as determined by flow cytometry, cell viability, and TUNEL assay. It was further shown that p53, one of the apoptosis-inducing transcription factors, was downregulated in the ATF3-overexpressing cardiomyocytes. These results strongly suggest that ATF3 may function as a cytoprotective transcription factor in DOX-treated cardiac myocytes, at least in part, owing to downregulation of p53. ATF3 may be a novel therapeutic target that protects cardiac myocytes from DOX-induced apoptosis.

Activating Transcription Factor 3↗
PubMed2002

Expression of matrix metalloproteinases in cardiac allograft vasculopathy and its attenuation by anti MMP-2 ribozyme gene transfection.

OBJECTIVE: Proliferation and migration of vascular smooth muscle cells (SMCs) causes intimal thickening during cardiac allograft vasculopathy (CAV). This process requires the degradation or remodeling of extracellular matrix (ECM) surrounding the cells. Imbalance between degradation and accumulation of ECM also contributes to the development of CAV. In this study, we investigated the contribution of matrix metalloprotenases (MMPs), enzymes regulating ECM turnover, to the development of CAV. METHODS: Donor hearts from male DBA mice were heterotopically transplanted to male B10.D2 recipient mice, and harvested at days 15 and 30 post transplantation. We examined expression MMP-2, -3, -9 and -13 of graft vessels using immunohistochemistry. To clarify the role of MMP-2 in CAV, anti MMP-2 ribozyme was delivered into donor hearts just before transplantation, mediated by a hemagglutinating virus of Japan-liposome complex to specifically suppress MMP-2 activity. RESULTS: All MMPs were immunopositive in SMCs from the slightly thickened neointima at day 15. In the advanced stage of intimal thickening at day 30, in addition to increased number of SMCs, accumulation of collagenous fibers was observed; expression of MMP-3, -9 and -13 was decreased. In contrast, MMP-2 expression remained distinctly positive throughout the progression of the vascular remodeling. After the gene transfer of MMP-2 ribozyme, luminal occlusion was significantly decreased compared to non-treated allografts [25.0+/-6.5 vs. 55.1+/-7.0% (P<0.05)] at day 30 post transplantation. CONCLUSION: MMP-2 is a principle MMP throughout the progression of the vascular remodeling in CAV. Anti MMP-2 therapy could therefore be one of the candidates for a supplemental therapy for CAV.

Animals↗
PubMed2002

Acute vigorous exercise primes enhanced NO release in human platelets.

Activation of platelets by acute vigorous exercise has been demonstrated by various parameters, including an increase in agonist-induced platelet [Ca2+]i levels. However, direct evidence is lacking regarding how acute exercise affects platelet-derived NO. Twenty-three healthy male non-smokers (21-59 years) underwent a symptom-limited treadmill exercise test. Washed platelets were prepared from blood samples obtained before and immediately after exercise. All subjects completed at least Bruce stage 2 and were each negative for ischemia. With a low dose (2 microg/ml) of collagen, NO release from washed platelets, detected by the NO-selective microelectrode, was significantly increased after exercise (pmols/10(8) platelets, before: 0.64+/-0.11, after: 1.03+/-0.18; P<0.005) without changes in aggregation ability. This enhanced NO release was accompanied by increased platelet [Ca2+]i levels (before: 232+/-25, after: 296+/-37; P<0.01). With a high dose (5 or 10 microg/ml) of collagen, NO release and aggregation were both modestly, but significantly, enhanced after exercise. The exercise-induced enhancement of platelet NO release in response to collagen was also suggested by increase in platelet cyclic guanosine monophosphate accumulation and augmenting effect of N(G)-monomethyl-L-arginine on platelet aggregation. In summary, acute strenuous exercise primes enhanced NO release and may play a protective role against exercise-induced activation of platelets in normal subjects.

Adult↗
PubMed2002

Smokers lack morning increase in platelet sensitivity to nitric oxide.

This study investigated whether a circadian variation is present in the sensitivity of platelets to nitric oxide (NO) and, if so, if long-term smoking modifies it. Blood samples were taken at 0:00, 6:00, 9:00, 12:00, and 18:00 from 14 nonsmokers and 10 smokers. Dose-response curves for platelet aggregation by collagen were constructed in both the presence and absence of 1.0 micro M of NOR-3, a NO donor. The antiaggregation properties of NOR-3 were quantified by the half maximal concentration (EC50) ratio in the presence of NOR-3 to that in its absence. Platelet aggregation showed a monophasic circadian rhythm, with the lowest levels at 6:00 and the highest at 18:00 in both groups. However, there was a significant (p < 0.01) upward shifting of platelet aggregation in the smokers. A circadian variation in sensitivity to NOR-3 also was demonstrated in the nonsmokers. The sensitivity was lowest at 6:00 (1.68 +/- 0.19), increased significantly at 9:00 (2.58 +/- 0.26; p < 0.01), and remained high at 12:00 (2.47 +/- 0.21; p < 0.05). In smokers, however, a circadian variation in platelet sensitivity to NOR-3 was not found. Furthermore, the sensitivity was significantly lower at 9:00 and 12:00 in smokers (1.94 +/- 0.26 and 1.76 +/- 0.13, respectively; p < 0.05 for both) than in nonsmokers. Thus, long-term smoking impairs the normal morning increase in platelet sensitivity to NO, making platelets in smokers more thrombogenic during the hazardous hours.

Adult↗
PubMed2002

Anti-arrhythmic efficacy of nifekalant hydrochloride, a pure class III anti-arrhythmic agent, in patients with healed myocardial infarction and inducible sustained ventricular tachycardia.

In recent clinical trials, class III anti-arrhythmic drugs were found to reduce arrhythmic deaths in patients after myocardial infarction. The purpose of this study was to assess the electrophysiologic properties and anti-arrhythmic efficacy for inducible sustained ventricular tachycardias (VTs) of the pure class III agent nifekalant hydrochloride (MS-551) in comparison with those of procainamide. Programmed ventricular stimulation of up to three extra stimuli was performed for induction of VTs. Effective refractory period (ERP) of the ischemic zone and normal zone was also measured before and after nifekalant. Nifekalant and procainamide suppressed sustained VT induction in four of 15 patients and in six of 15 patients, respectively (p = NS). Sinus cycle length, PR interval, and QRS duration were not changed, but QT and QTc intervals were significantly increased with nifekalant (p < 0.01). Ventricular ERP also increased, whereas there were no significant differences in the increase of ERP between the ischemic and normal zones. The suppression of VT induction did not correlate with the changes in QT, QTc, and ERP after nifekalant administration. There were no significant differences in induced VT cycle length at baseline study between responders and nonresponders to nifekalant. Reverse use dependence was not apparent on review of electrophysiologic parameters. Neither proarrhythmic events nor hemodynamic disturbances occurred after nifekalant administration. It was concluded that nifekalant could be used safely and showed comparable effectiveness to procainamide for the suppression of VT induction.

Adult↗
PubMed2002

Expression of nonmuscle myosin heavy chain B (SMemb) in rat allogeneic kidney transplantation.

BACKGROUND/AIM: Investigators have reported that the nonmuscle myosin heavy chain B (SMemb) expression is enhanced in various types of glomerular diseases which develop into nephrosclerosis. In renal transplantation, transplant glomerulitis is often recognized during acute rejection. Therefore, we hypothesized that SMemb plays important roles in acute kidney rejection. To evaluate the role of SMemb in the development of kidney rejection, we examined its expression in rat kidney transplantation models. METHODS: We used Lewis rats as recipients and Wistar rats as donors. Group I: controls; group II: isograft model; group III: allograft model; group IV: as group III +10 mg/kg/day of ciclosporin A (CsA), and group V: as group III + CsA administration for 5 days postoperatively. Histopathological and SMemb immunohistochemical studies were completed. RESULTS: Clear enhancement of SMemb expression was found on day 3 in group III. In groups I, II, IV, and V, SMemb was faintly expressed in the glomerular cells. However, after termination of CsA treatment, the SMemb expression increased. The expression of SMemb was higher in the allograft model than in either isograft or CsA-treated models. CONCLUSIONS: Immunohistological investigations show that the SMemb expression was significant from an early stage at which histopathological reactions were hardly identifiable. This, therefore, could be useful for an earlier diagnosis of acute rejection.

Acute Disease↗
PubMed2002

National survey of fulminant myocarditis in Japan: therapeutic guidelines and long-term prognosis of using percutaneous cardiopulmonary support for fulminant myocarditis (special report from a scientific committee).

Although fulminant myocarditis is known as a fatal disease, patients have been able to recover and return to normal life with the help of mechanical cardiopulmonary support. However, therapeutic guidelines for using percutaneous cardiopulmonary support (PCPS) for fulminant myocarditis have not been established, and the clinical course and long-term prognosis of such patients are still controversial issues. The present national survey considered the current situation of patients as the basis for proposing therapeutic guidelines. Thirty of 52 patients (57.7%) survived and returned to social life. Important factors concerning the prognosis were the severity and grade of cardiac and renal dysfunction, the adjusted support flow rate to enable recovery from circulatory failure, and prevention of circulatory disturbances of the legs and multiple organ failure directly associated with PCPS. With regard to the long-term prognosis of patients treated with PCPS, the readmission rate was 10%, the exacerbation rate was 3.3%, and mortality was 10% during the average follow-up period of 962 days. Optimal management of the mechanical cardiopulmonary support and curative treatment for the myocarditis further improve the outcome of this disease.

Blood Gas Analysis↗
PubMed2002

Opening of K(ATP) channel attenuates the increase in QT dispersion produced by the first balloon inflation during coronary angioplasty.

Increased QT dispersion predicts the occurrence of lethal ventricular arrhythmias complicating percutaneous transluminal coronary angioplasty (PTCA). Moreover, these arrhythmias occur more frequently at the first balloon inflation. Activation of the K(ATP) channel may influence QT dispersion and ventricular arrhythmias during coronary angioplasty, so 40 consecutive patients with stable angina were randomized to receive 3 mg/h of nicorandil infusion or placebo and QT dispersion and the incidence of ventricular ectopy were investigated before and throughout PTCA. There were no significant differences in QT dispersion at baseline between the nicorandil group (42+/-8 ms) and placebo (42+/-12ms). At the first balloon inflation, the QT dispersion in the nicorandil group (51+/-13 ms) was significantly less than that observed with placebo (76+/-16ms, p<0.001). However, the QT dispersion at the second inflation was similar in both groups (nicorandil: 45+/-12ms; placebo: 52+/-14ms). Ventricular ectopy was observed in 1 patient receiving nicorandil and 5 patients in the placebo group during the first inflation, and none in the nicorandil and 1 patient in the placebo group during the second balloon inflation. Activation of the K(ATP) channel may inhibit the development of ventricular arrhythmias during PTCA, particularly at the first balloon inflation.

Adenosine Triphosphate↗
PubMed2002

Delayed thrombogenesis following radiofrequency catheter ablation.

The cause and duration of the thrombogenesis provoked by radiofrequency catheter ablation (RF-CA) was investigated by measuring the thrombin-antithrombin III complex (TAT) in 43 patients who underwent RF-CA and in 20 control subjects who underwent an electrophysiologic study. Blood samples were collected at 7 different times: before introducing the sheaths, during the ablation procedure and at 30 min, 6 and 24h, and 3 and 6 days after the procedure. Hepatocyte growth factor (HGF) was simultaneously measured in the ablation group. Plasma TAT concentration exhibited a double peaked pattern in the ablation group: the first peak occurred during the ablation procedure (42.8+/-15.5 ng/ml), and the second peak 3 days later. Plasma TAT at 3 days after the procedure was significantly higher than that of the control group (21.3+/-19.0 vs 2.5+/-1.4, p=0.0003). The first peak significantly correlated with the procedure time prior to the administration of heparin (r=0.669), but the second peak did not (r=0.132). A subgroup with a serum HGF >0.40 ng/ml at 6 h after the procedure exhibited a significantly high second peak. The thrombogenesis caused by RF-CA has 2 phases; in the acute phase, there is hemostasis during placement of the catheters, and in the delayed phase thrombogenesis is the result of endothelial damage from the RF current.

Adult↗
PubMedDate not supplied

Suppression of experimental autoimmune uveoretinitis by anti-alphabeta TCR monoclonal antibody.

PURPOSE: To evaluate the effects of anti-alphabeta T cell receptor monoclonal antibody (R73) on the induction of experimental autoimmune uveoretinitis (EAU) in rats. METHODS: Lewis rats in which EAU was induced were treated with R73. All rats were examined for the clinical course of EAU, pathological findings of the globe, delayed-type hypersensitivity, and the interleukin-2 (IL-2) gene and protein expression in the eye. RESULTS: The R73 treatment was effective for delaying EAU onset, decreasing the severity of EAU, and suppressing delayed-type hypersensitivity to the antigen. IL-2 gene and protein expression was reduced by R73 treatment in the anterior and posterior segments of the eye. CONCLUSION: R73 treatment is effective for suppression of the development of EAU, inhibiting IL-2 expression in the eye.

Animals↗