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Seiji Umemoto

Publications and source records attributed to Seiji Umemoto.

15 recordsLinked to original sources
PubMed2006

Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-gamma, and aortic stiffness in hypercholesterolemia.

Reactive oxygen species-scavenging enzyme Cu/Zn superoxide dismutase (SOD) regulated by peroxisome proliferator-activated receptors (PPARs) plays an important role in vascular responsiveness. However, it remains unknown whether statin restores vascular dysfunction through the activation of reactive oxygen species-scavenging enzymes in vivo. We hypothesized that pitavastatin restores vascular function by modulating oxidative stress through the activation of Cu/ZnSOD and PPAR-gamma in hypercholesterolemia. New Zealand White male rabbits were fed either normal chow or a 1% cholesterol (CHO) diet for 14 wk. After the first 7 wk, the CHO-fed rabbits were further divided into three groups: those fed with CHO feed only (HC), those additionally given pitavastatin, and those additionally given an antioxidant, probucol. The extent of atherosclerosis was assessed by examining aortic stiffness. When compared with the HC group, both the pitavastatin and probucol groups showed improved aortic stiffness by reducing aortic levels of reactive oxidative stress, nitrotyrosine, and collagen, without affecting serum cholesterol or blood pressure levels. Pitavastatin restored both Cu/ZnSOD activity (P < 0.005) and PPAR-gamma expression and activity (P < 0.01) and inhibited NAD(P)H oxidase activity (P < 0.0001) in the aorta, whereas probucol inhibited NAD(P)H oxidase activity more than did pitavastatin (P < 0.0005) without affecting Cu/ZnSOD activity or PPAR-gamma expression and activity. Importantly, Cu/ZnSOD activity was positively correlated with the PPAR-gamma activity in the aorta (P < 0.005), both of which were negatively correlated with aortic stiffness (P < 0.05). Vascular Cu/ZnSOD and PPAR-gamma may play a crucial role in the antiatherogenic effects of pitavastatin in hypercholesterolemia in vivo.

Animals↗
PubMed2006

Different effects of amlodipine and enalapril on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase pathway for induction of vascular smooth muscle cell differentiation in vivo.

Although recent clinical trials have shown that amlodipine exerts antiatherogenic effects, the mechanism of these effects remains unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Stroke-prone spontaneously hypertensive rats (SHRSP) were randomly treated with a vehicle, amlodipine, or enalapril while Wistar-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure, and inhibiting the progression of aortic remodeling and fibrosis in comparison to those of vehicle-treated SHRSP. In the aortas of vehicle-treated SHRSP, the level of contractile-type smooth muscle (SM) myosin heavy chain (MHC) SM2 was significantly lower, whereas the level of synthetic-type MHC NMHC-B/SMemb was significantly higher compared with those in the WKY aortas. Compared to the vehicle-treated SHRSP group, both drugs significantly and equally shifted the aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, the levels of MEK1 and p-42/44 ERK were significantly lower in the amlodipine- than in the enalapril-treated SHRSP group, whereas enalapril was more effective than amlodipine at increasing p-Akt and endothelial NO synthase in SHRSP aortas, which were significantly lower in the vehicle SHRSP group than in the WKY group. Thus, the MEK-ERK pathway might be one of the crucial determinants of the aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo.

Amlodipine↗
PubMed2006

[COPE trial].

Explore the source record for details and available documents.

Adrenergic beta-Antagonists↗
PubMed2005

Up-regulation of Akt and eNOS induces vascular smooth muscle cell differentiation in hypertension in vivo.

Recent studies have shown that angiotensin II type 1 (AT1) receptor-mediated Akt activation induces vascular smooth muscle cell (VSMC) dedifferentiation in vitro. However, the critical signal transductions affecting the VSMC phenotype remain unclear in vivo. We examined whether signal transduction through AT1 receptor-mediated reactive oxygen species (ROS) could regulate the VSMC phenotype in stroke-prone spontaneously hypertensive rats (SHRSPs). Male SHRSPs were randomized and treated for 6 weeks with a vehicle, an ACE inhibitor cilazapril, or an AT1 receptor antagonist E4177. The 2 drugs showed equipotent effects on the blood pressure, aortic morphology, and collagen deposition. Both drugs also significantly reduced aortic NAD(P)H oxidase activity and p38MAPK and ERK expression, whereas p-Akt, eNOS, and SM2 were significantly increased in SHRSP aortas. Furthermore, E4177 was more effective than cilazapril at inducing VSMC differentiation by reducing NAD(P)H oxidase activity, and up-regulating p-Akt, eNOS, and SM2. Thus, an ACE inhibitor and an AT1 receptor antagonist inhibited VSMC dedifferentiation through inhibition of NAD(P)H oxidase activity and up-regulation of eNOS and Akt in SHRSP aortas, suggesting that in contrast to the in vitro experiments, AT1 receptor-mediated NAD(P)H oxidase-generated ROS, eNOS, and Akt might be crucial determinants for the VSMC phenotype in hypertension in vivo.

Animals↗
PubMed2005

The combination therapy of hypertension to prevent cardiovascular events (COPE) trial: rationale and design.

A number of major clinical trials have demonstrated the clinical benefits of lowering blood pressure and have indicated that a majority of patients with hypertension will require more than one drug to achieve optimal blood pressure control. However, there is little data showing which antihypertensive combination best protects patients from cardiovascular events and which best achieves the target blood pressure with the fewest adverse events. The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial is the first large-scale investigator-initiated multicenter study with a prospective, randomized, open, blinded endpoint evaluation (PROBE) design to directly compare cardiovascular mortality and morbidity, incidence of adverse drug reaction, and degree of blood pressure reduction in Japanese hypertensive patients for a combination of angiotensin receptor blockers, beta-blockers or thiazide diuretics in addition to a calcium antagonist, benidipine hydrochloride, with a response-dependent dose titration scheme. The COPE trial is being conducted with the cooperation of more than 100 centers and clinics in Japan and involves 3,000 patients, who will be followed for 3 years. Eligible patients are being enrolled from May 2003 until May 2006. Results from the COPE trial should provide new evidence for selecting optimal combination therapies for hypertensive patients.

Antihypertensive Agents↗
PubMed2005

Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats.

Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Identification of autoantibodies with the corresponding antigen for repetitive coxsackievirus infection-induced cardiomyopathy.

BACKGROUND: The hypothesis that viral myocarditis causes an autoimmune response and subsequent dilated cardiomyopathy is controversial. To further investigate the autoimmune mechanism of cardiac dilatation and dysfunction after repeated episodes of viral myocarditis, the cardiac autoantigens induced by repetitive coxsackievirus B3 (CVB3) infection were examined. METHODS AND RESULTS: Male inbred A/J mice were inoculated intraperitoneally with CVB3 at 3 and 40 weeks of age. At 8 weeks after the second inoculation, the mortality of the repetitive CVB3 group was significantly increased compared with that of the control group, and was associated with a significant reduction in fractional shortening and marked left ventricular dilatation without inflammatory cell infiltration. The cardiac antigens in the repetitive CVB3 infection were identified by 2-dimensional electrophoresis and subsequent liquid chromatography/tandem mass spectrometry (LC-MS/MS) using the serum at 2 weeks after the second inoculation. LC-MS/MS and immunohistochemistry demonstrated alpha-cardiac actin and heat shock protein 60 (HSP60) as cardiac near-surface antigens induced by the repetitive CVB3 infection. Immunoelectron microscopy disclosed the selective localization of anti-IgM antibody on the membrane of the myocytes in the repetitive CVB3 group. CONCLUSIONS: IgM antibodies against alpha-cardiac actin and HSP60, which were induced by repetitive CVB3 infection, may play an important role in the pathophysiology of the subsequent cardiac dysfunction and dilatation.

Animals↗
PubMed2004

Effects of angiotensin II type 1 receptor antagonist on smooth muscle cell phenotype in intramyocardial arteries from spontaneously hypertensive rats.

To clarify the precise mechanisms involved in the reduced coronary flow reserve in hypertension, we compared the effects of the angiotensin II type 1 (AT1) receptor antagonist FK-739 with those of the angiotensin-converting enzyme (ACE) inhibitor enalapril for 6 weeks on the smooth muscle (SM) cell phenotype in intramyocardial arteries from male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Compared with WKY, SHR showed a significant increase in left ventricular (LV) hypertrophy and fibrosis, blood pressure (BP), and vascular remodeling of the intramyocardial arteries, and a significant decrease in endothelial NO synthase and the contractile-type myosin heavy chain isoform SM2 of the intramyocardial arteries as well as calponin 1 and GATA-6. In the hearts of SHR, both drugs equivalently and significantly reduced BP, which was still significantly higher than that in the WKY groups, and also reduced LV hypertrophy and fibrosis, whereas endothelial NO synthase was significantly restored. Although both drugs showed little effect on the vascular remodeling of the intramyocardial arteries in the SHR hearts, FK-739, but not enalapril, significantly restored SM2 and GATA-6 in the SHR hearts to the same levels as those of the vehicle WKY group. The effects of the two drugs on these indices were not observed in the three WKY hearts. Thus, the AT1 receptor antagonist may modulate the SM cell phenotype toward the contractile-type more effectively than the ACE inhibitor before the morphological changes occur in the intramyocardial arteries of the SHR hearts.

Actins↗
PubMed2004

Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats.

Recent studies have suggested that the calcium antagonists have an antiatherogenic antioxidant property. The effects of the calcium antagonists on reactive oxygen species (ROS)-related enzymes, however, remain unknown. We hypothesized that the calcium antagonists inhibit oxidative stress in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) through the ROS-scavenging enzymes known as superoxide dismutases (SODs). Male 12-week-old Wister-Kyoto rats (WKY) and SHRSP were used for the study. SHRSP were randomized and treated for 6 weeks with a vehicle, amlodipine (5 mg/kg/day), or enalapril (10 mg/kg/day). NAD(P)H oxidase activity was measured by a luminescence assay, and SOD activity was measured spectrophotometrically. Protein expressions were analyzed by immunoblots. Both drugs showed equipotent effects on systolic blood pressure, left ventricular hypertrophy and fibrosis, the wall-to-lumen ratio, the manganese SOD activity, ROS, and the endothelial NO synthase expression in the SHRSP hearts. Furthermore, amlodipine significantly restored copper/zinc-containing SOD (Cu/ZnSOD) expression and its activity in SHRSP hearts to a level equal to that of WKY more effectively than did enalapril (p <0.05), whereas enalapril downregulated NAD(P)H oxidase activity more than did amlodipine (p <0.05) in the SHRSP hearts. Furthermore, amlodipine restored Cu/ZnSOD expression and its activity in SHRSP hearts to a level equal to that in WKY hearts, and this restoration was significantly more effective than that by enalapril (p <0.05); on the other hand, enalapril induced a greater downregulation of NAD(P)H oxidase activity in SHRSP hearts than did amlodipine (p <0.05). Thus, amlodipine may inhibit vascular remodeling and oxidative stress in the SHRSP heart by efficiently upregulating Cu/ZnSOD, suggesting that the calcium antagonist may exhibit an antiatherogenic antioxidative action beyond blood-pressure lowering through the restoration of Cu/ZnSOD activity in the heart in cases of hypertension.

Amlodipine↗
PubMed2004

[Benefits of candesartan in the treatment of symptomatic heart failure--CHARM programme].

The CHARM programme, which recruited 7,601 patients, compared the angiotensin-receptor blocker, candesartan, with a placebo in three different populations with class II-VI heart failure. Candesartan reduced cardiovascular mortality and/or hospitalization for heart failure in patients with heart failure and ejection fractions of greater than 40% or less, and total mortality was reduced in these patients as well. Similar benefits were seen whether or not background therapy with ACE inhibitors, beta blockers', or spironolactone was used. Pooled analysis of the three studies showed that candesartan provided a significant reduction in cardiovascular death and also demonstrated a positive trend in the overall reduction in all cause mortality. The major adverse effects were hyperkalemia, increase in creatinine concentration and hypotension.

Antihypertensive Agents↗
PubMed2003

Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model.

OBJECTIVES: The present study investigated the effects of tumor necrosis factor (TNF)-alpha and angiotensin II (ANG II) on cardiac remodeling and dysfunction at the early stage of acute myocardial infarction (MI) by using a novel heterotopic cardiac transplantation-coronary ligation model. BACKGROUND: A recent clinical study has demonstrated a possible role of monocytosis in the development of left ventricular (LV) remodeling in patients with acute MI reperfusion. METHODS: We performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce MI in the donor heart and to evaluate the hearts of both donors and recipients in Lewis rats. RESULTS: A significant decrease in LV fractional shortening and positive rate of rise in LV pressure and a significant increase in LV end-diastolic dimension/body weight and LV end-diastolic pressure were observed in the recipient hearts in the ligation group on day 7. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group. In contrast, ANG II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Furthermore, the recipients' transient LV remodeling and dysfunction were completely abolished by the intravenous administration of a TNF-alpha antagonist. CONCLUSIONS; We developed a novel cardiac transplantation-coronary ligation model capable of inducing MI in the absence of downstream hemodynamic effects and allowing differential quantification of indexes of cardiac remodeling in vivo, including the local and remote effects of ANG II and TNF-alpha on cardiac remodeling.

Angiotensin II↗
PubMed2003

Effect of suplatast tosilate, an antiallergic selective Th2 cytokine inhibitor, on acute eosinophilic myocarditis: a case report.

We encountered a 44-year-old woman with acute eosinophilic myocarditis that showed positive immunostaining for interleukin-4 in the area of marked infiltration of eosinophils into the myocardium. When prednisolone alone proved ineffective, supplementary treatment with suplatast tosilate, an antiallergic selective Th2 cytokine inhibitor, improved the patient's inflammation, reduced the level of cardiac enzymes, and allowed for a reduction in corticosteroid dosage without any adverse effects.

Acute Disease↗
PubMed2003

[Induction of left ventricular remodeling and dysfunction in the recipient heart following donor heart myocardial infarction: new insights into the pathological role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation model].

BACKGROUND: Neurohormonal and cytokine activation after acute myocardial infarction contribute to cardiac remodeling. This study aimed to examine the effects of tumor necrotic factor (TNF)-alpha and angiotensin II on cardiac remodeling and dysfunction after acute myocardial infarction. METHODS AND RESULTS: We performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce myocardial infarction in the donor heart, and to evaluate the hearts of both donors and recipients in Lewis rats. The recipients in the ligation group showed significant body-weight loss, hyperthermia, tachycardia, hypotension and leukocytosis at day 7. A significant decrease in left ventricular fractional shortening and + dP/dt, and a significant increase in left ventricular enddiastolic dimension/body weight and left ventricular enddiastolic pressure were also observed in the recipient hearts in the ligation group at day 7. With the exception of the increased perivascular fibrosis, these recipient responses were no longer seen at day 21. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group at day 7. In contrast, angiotensin II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Further, the recipients' transient left ventricular remodeling and dysfunction were completely abolished by the intravenous administration of chimeric TNF-alpha soluble receptor. CONCLUSIONS: We developed a novel heterotopic cardiac transplantation-coronary ligation model capable of inducing myocardial infarction in the absence of downstream hemodynamic effects, and allowing differential quantification of indexes of cardiac remodeling in vivo, such as the local and remote effects of angiotensin II and TNF-alpha on cardiac remodeling. Modification of activated cytokines, such as TNF-alpha induced by cardiac ischemic stress, might be a beneficial strategy for the treatment of cardiac dysfunction and subsequent cardiac remodeling after acute myocardial infarction.

Angiotensin II↗
PubMed2002

Importance of NAD(P)H oxidase-mediated oxidative stress and contractile type smooth muscle myosin heavy chain SM2 at the early stage of atherosclerosis.

BACKGROUND: Increased vascular oxidative stress induced by hyperlipidemia may alter the phenotype of vascular smooth muscle (SM) cells and play a crucial role in the progression of atherosclerosis. To clarify the mechanisms underlying vascular dysfunction and oxidative stress in hypercholesterolemia, we compared the effects of antioxidant probucol with those of pravastatin on aortic stiffness, phenotypic modulation, oxidative stress, and NAD(P)H oxidase essential subunit p22(phox) expression in aortic medial SM cells of cholesterol-fed rabbits by using color image analysis of immunostained sections. METHODS AND RESULTS: Japanese white male rabbits were fed either normal chow or 1% cholesterol diet for 14 weeks. After the first 7 weeks, cholesterol-fed rabbits were further divided into 3 groups: those fed with cholesterol feed only and those additionally given pravastatin (10 mg/d) or probucol (1.3 g/d) for the last 7 weeks. Within 7 weeks of treatment, probucol improved aortic stiffness more effectively than did pravastatin, inhibiting phenotypic modulation by selectively upregulating contractile-type SM myosin heavy chain isoform SM2 and by reducing both p22(phox) and superoxide content in medial SM cells of cholesterol-fed rabbit aorta. No significant differences in cholesterol levels, superoxide content, and endothelial NO synthase levels in the intima, aortic morphology and fibrosis, and synthetic-type myosin heavy chain in medial SM cells were observed between the 2 drug-treated groups. CONCLUSIONS: These results suggest that oxidative stress and SM2 in medial SM cells might be important factors for vascular dysfunction, and strategies aimed at blocking NAD(P)H oxidase and upregulating SM2 may have therapeutic potential against the progression of atherosclerosis in hypercholesterolemia.

Actins↗