Taizo Kimura

Yamaguchi University, Yamaguti, Yamaguchi, Japan

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Publications (15)35.2 Total impact

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    ABSTRACT: We aimed to investigate the anti-hypertensive effect of radiofrequency (RF) renal denervation (RDN) in an animal model of hypertension.
    Life sciences. 06/2014;
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    ABSTRACT: Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Experimental autoimmune myocarditis (EAM) is a mouse model of post-infectious myocarditis and inflammatory cardiomyopathy. The pathological role of endothelin (ET) in myocarditis has not been elucidated. EAM was induced by immunization of cardiac myosin peptide with complete Freund's adjuvant on days 0 and 7 in BALB/c mice. An ETA/ETB dual receptor antagonist, SB209670, was administered by a continuous infusion from a subcutaneous pump for 2 weeks. An increase in the heart-to-body weight ratio was observed in SB209670-treated mice compared with vehicle-treated mice. The heart pathology in SB209670-treated mice was remarkable for gross inflammatory infiltration, in contrast to the lesser inflammation in the hearts of vehicle-treated mice. We found that an ET blockade decreased the number of Foxp3(+) regulatory T cells in the heart. The ET blockade also inhibited the expression of the suppressor of cytokine signaling 3 that plays a key role in the negative regulation of both Toll-like receptor- and cytokine receptor-mediated signaling. EAM is a CD4(+) T cell-mediated disease. CD4(+) T cells isolated from SB209670-treated EAM mice produced less IL-10 and more inflammatory cytokines, IL-6 and IL-17, than those isolated from vehicle-treated mice. The ET receptor antagonist exacerbated autoimmune myocarditis in mice. Our novel findings may suggest that ET plays an important role in the regulation of inflammation in myocarditis.
    Life sciences 01/2014; · 2.56 Impact Factor
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    ABSTRACT: Aims Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We investigated the ameliorating effect of CGRP in myocardial ischemia induced by endothelin-1 (ET-1), with special emphasis on myocardial microvascular hemodynamics and levels of energy-related metabolites. Main Methods Langendorff preparations of rat isolated heart were perfused at a constant flow rate. Microvascular blood flow was also visualized in the anterior epicardium of the left ventricle by means of an intravital fluorescence microscope system. Energy-related metabolite contents in the myocardium were measured by means of 31P-magnetic resonance spectroscopy (31P-MRS). Key Findings Intracoronary bolus injections of CGRP caused dose-dependent decreases in coronary perfusion pressure (CPP) in hearts exposed to ET-1 (30 pmol). The vasodilator potency of CGRP was about 1000-fold greater than that of nitroglycerin and 100-fold greater than that of isobutylmethylxanthine. Vasodilation of the small-sized arterioles (10–40 μm in diameter) in response to CGRP (100 pmol) was confirmed by direct microscopic observation. After ET-1 (30 pmol) plus vehicle administration, high energy phosphates (phosphocreatine (PCr), ATP) were markedly reduced (p < 0.05). CGRP administration significantly (p < 0.05) attenuated the anaerobic changes in the myocardium (decrease in PCr) and macrohemodynamic alterations (increase in CPP, decrease in dP/dt etc.) induced by ET-1. Significance We conclude that CGRP effectively confers hemodynamic and metabolic protection to isolated beating hearts against ET-1-induced myocardial ischemia.
    Life sciences 01/2014; · 2.56 Impact Factor
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    ABSTRACT: Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl2 caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGFβ signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress.
    Scientific Reports 01/2014; 4:4051. · 5.08 Impact Factor
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    ABSTRACT: Aims Cardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit cardiac hypertrophy partly via the anti-oxidative stress. One of the common intracellular pathways of them is the phosphorylation cascade of MEK signaling. Pin1 specifically isomerizes the phosphorylated protein with Ser/Thr-Pro bonds and regulates their activity through conformational changes. There is no report whether the Pin1 activation contributes to ET-1-induced cardiomyocyte hypertrophy and whether the Pin1 inactivation contributes to the inhibitory effect of statins. The aim of this study was to reveal these questions. Main methods We assessed neonatal rat cardiomyocyte hypertrophy using ET-1 and fluvastatin by the cell surface area, ANP mRNA expression, JNK and c-Jun phosphorylation, and [3H]-leucine incorporation. Key findings Fluvastatin inhibited ET-1-induced increase in the cell surface area, ANP expression, and [3H]-leucine incorporation; and it suppressed the signaling cascade from JNK to c-Jun. The phosphorylated Pin1 level, an inactive form, was decreased by ET-1; however, it became basal level by fluvastatin. Furthermore, Pin1 overexpression clearly elicited cardiomyocyte hypertrophy, which was inhibited by fluvastatin. Significance This is the first report that ET-1-induced cardiomyocyte hypertrophy is mediated through the Pin1 activation and that the inhibitory effect of fluvastatin on cardiomyocyte hypertrophy would partly be attributed to the suppression of the Pin1 function. This study firstly suggests that Pin1 determines the size of hypertrophied cardiomyocyte by regulating the activity of phosphorylated molecules and that statins exert their pleiotropic effects partly via Pin1 inactivation.
    Life sciences 01/2014; · 2.56 Impact Factor
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    ABSTRACT: Post-procedural myocardial necrosis manifested by elevated cardiac troponin T (cTnT) often complicates percutaneous coronary intervention (PCI). Plasma pentraxin 3 (PTX3) levels are increased in patients with arterial inflammation and especially unstable angina pectoris (AP). This study tested whether plasma PTX3 levels can predict post-PCI cTnT elevation. We evaluated 94 consecutive patients with AP and normal pre-PCI cTnT levels who underwent PCI. Pre-PCI virtual histology-intravascular ultrasound was performed to assess culprit plaque composition. Plasma PTX3 and serum hs-CRP levels were measured pre PCI. Patients were divided into 2 groups according to presence (Group I, n=34) or absence (Group II, n=60) of post-PCI cTnT elevation >3× the upper limit of normal at 24hours after PCI. Plasma PTX3 (4.06±2.05ng/ml vs 2.17±1.02ng/ml, p<0.001), serum hs-CRP levels (0.25±0.03 vs 0.16±0.03mg/dl, p=0.048), plaque burden (80.9±5.3 vs 75.4±10.6%, p=0.047), presence of positive remodeling (59 vs 25%, p=0.034), and percent necrotic core area (19.0±7.4 vs 14.0±5.9%, p=0.046) were significantly higher in Group I than in Group II. Receiver-operating characteristic curve analysis showed that with a best cut-off value of 2.83ng/ml, plasma PTX3 level (AUC 0.823) predicted post-PCI cardiac TnT elevation better than did serum hs-CRP level (AUC 0.618). Multiple logistic regression analysis showed that plasma PTX3 level was the most independent predictor of post-PCI cardiac cTnT elevation (OR: 2.65; 95% CI: 1.56-10.1; p=0.003). Plasma PTX3 level may be a useful marker for predicting post-PCI cardiac cTnT elevation, which is associated with inflammatory status of culprit lesions.
    Life sciences 12/2013; · 2.56 Impact Factor
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    ABSTRACT: PURPOSE: Experimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy, and the involvement of T helper (Th) 1 and Th17 cytokines has been demonstrated. Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; however, the mechanism has not been fully elucidated. This study was designed to test the hypothesis that pitavastatin affects T cell-mediated autoimmunity through inhibiting Th1 and Th17 responses and reduces the severity of EAM in mice. METHODS: The EAM model was established in BALB/c mice by immunization with murine α-myosin heavy chain. Mice were fed pitavastatin (5 mg/kg) or vehicle once daily for 3 weeks from day 0 to day 21 after immunization. RESULTS: Pitavastatin reduced the pathophysiological severity of the myocarditis. Pitavastatin treatment inhibited the phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT4, which have key roles in the Th1 and Th17 lineage commitment, respectively, in the heart, and suppressed production of Th1 cytokine interferon-γ and Th17 cytokine interleukin-17 from autoreactive CD4(+) T cells. In in vitro T-cell differentiation experiments, pitavastatin-treated T cells failed to differentiate into Th1 and Th17 cells through inhibiting the transcription of T-box expressed in T-cells (T-bet) and RAR-related orphan receptor γt (RORγT) which have critical roles in the development of Th1 and Th17 cells, respectively, and this failure was rescued by adding mevalonate. CONCLUSIONS: Pitavastatin inhibits Th1 and Th17 responses and ameliorates EAM. These results suggest that statins may be a promising novel therapeutic strategy for the clinical treatment of myocarditis and inflammatory cardiomyopathy.
    Cardiovascular Drugs and Therapy 05/2013; · 2.67 Impact Factor
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    ABSTRACT: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome and its etiology and pathogenesis have not been well understood. Intracoronary imaging modalities with intravascular ultrasound and optical coherence tomography would enable a precise diagnosis in this entity. Coronary angioscopy is also a unique tool for allowing direct visualization of the luminal surface of a vessel. We described an interesting case of SCAD documented with multimodality intracoronary imaging showing the presence of superficial lipid plaque nearby the coronary dissection entry point, which might have been associated with fragility of the arterial wall and the subsequent development of SCAD. © 2012 Wiley Periodicals, Inc.
    Catheterization and Cardiovascular Interventions 07/2012; · 2.51 Impact Factor
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    ABSTRACT: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is not normally expressed in the adult heart but transiently reappears under various pathologic conditions to play important roles in tissue remodeling. It is unclear whether serum TN-C levels add prognostic information independent from traditional prognostic markers. We assessed 239 patients with first ST-segment elevation myocardial infarction who underwent successful percutaneous coronary intervention. We measured serum TN-C and plasma B-type natriuretic peptide (BNP) levels on day 5 after admission and compared long-term clinical outcome. During the follow-up period (24.3 ± 13 months), 54 patients experienced primary composite cardiac events (cardiac death or hospitalization for worsening heart failure). Multivariable Cox proportional hazards analysis indicated that serum TN-C (hazard ratio 2.92, 95% confidence interval [CI] 1.55-5.67; P < .001) and plasma BNP levels (hazard ratio 1.84, 95% CI 1.17-2.97; P = .008) were significant independent predictors for cardiac events after adjustment for multiple confounders. The combination of TN-C and BNP resulted in an increase of the c-statistic from 0.821 to 0.877 (P < .001) and an integrated discrimination improvement gain of 14.0% (P < .001). Serum TN-C level on day 5 after admission is potentially useful for early risk stratification after AMI beyond established prognostic markers.
    Journal of cardiac failure 06/2012; 18(6):480-6. · 3.25 Impact Factor
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    ABSTRACT: Cardiac hypertrophy is associated with the increase of total amount of RNA, which is in accordance with RNA polymerase II (RNAPII) activation via C-terminal domain (CTD) phosphorylation of the largest subunit of RNAPII. It has been demonstrated that endothelin-1 (ET-1) phosphorylates CTD at the hypertrophic response in cardiomyocytes. However, it is unclear whether ET-1-induced hypertrophy is affected by the CTD phosphatase, transcription factor IIF-interacting CTD phosphatase1 (FCP1). We analyzed whether ET-1-induced cardiomyocyte hypertrophy was affected by overexpression of FCP1 or dominant-negative form of FCP1 (dnFCP1) in neonatal rat cardiomyocytes. The level of ET-1-induced RNAPII CTD phosphorylation was decreased by FCP1 overexpression, whereas it was sustained by dnFCP1. Global RNA synthesis evaluated by [(3)H]-uridine incorporation showed that the ET-1-induced increase in RNA synthesis was suppressed by FCP1 and was augmented by dnFCP1. ET-1-induced increase in cell surface area was suppressed by FCP1 and was preserved by dnFCP1. Furthermore, the ET-1-induced increase in molecular markers of cardiac hypertrophy, expression of ANP and β-MHC gene, was suppressed by FCP1 and was not inhibited by dnFCP1. ET-1-induced cardiac hypertrophy and CTD phosphorylation level are functionally regulated by FCP1. These findings suggest that FCP1 plays an important role in ET-1-induced cardiac hypertrophy via controlling phosphorylation level of the RNAPII CTD.
    Life sciences 04/2012; 91(13-14):572-7. · 2.56 Impact Factor
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a common disease caused by segmental weakening of the aortic walls and progressive aortic dilation leading to the eventual rupture of the aorta. Currently no biomarkers have been established to indicate the disease status of AAA. Tenascin-C (TN-C) is a matricellular protein that is synthesized under pathological conditions. In the current study, we related TN-C expression to the clinical course and the histopathology of AAA to investigate whether the pattern of TN-C expression could indicate the status of AAA. We found that TN-C and matrix metalloproteinase (MMP)-9 were highly expressed in human AAA. In individual human AAA TN-C deposition associated with the tissue destruction, overlapped mainly with the smooth muscle actin-positive cells, and showed a pattern distinct from macrophages and MMP-9. In the mouse model of AAA high TN-C expression was associated with rapid expansion of the AAA diameter. Histological analysis revealed that TN-C was produced mainly by vascular smooth muscle cells and was deposited in the medial layer of the aorta during tissue inflammation and excessive destructive activities. Our findings suggest that TN-C may be a useful biomarker for indicating the pathological status of smooth muscle cells and interstitial cells in AAA.
    Pathology International 10/2011; 61(10):559-64. · 1.72 Impact Factor
  • Taizo Kimura, Shigeyuki Watanabe
    Nippon rinsho. Japanese journal of clinical medicine 10/2007; Suppl 5 Pt 2:228-33.
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    ABSTRACT: Magnetocardiography (MCG) is sensitive to minute cardiac electric abnormalities, but its clinical utility in diagnosing ischemic heart disease (IHD) has not been established. The present study examined the usefulness of an integral MCG value of ventricular repolarization in patients with IHD. MCG was performed at rest in 14 patients with coronary stenosis >75% confirmed by coronary angiography (IHD group) using a 64-channel system, and then the sum of the 64-channel integral values of the QRS or JT intervals (QRSi and JTi, respectively) was calculated. The JTi/QRSi value indicated the total power of currents in JT compared with those in QRS. These measurements were repeated within 2 weeks after coronary revascularization. The Control group comprised 30 healthy volunteers. The baseline value of JTi/QRSi was significantly smaller in the IHD than in the Control group, but after revascularization it increased and did not significantly differ from the Control group. No significant difference in ST deviation was identified by electrocardiography (ECG) before and after coronary revascularization. Analysis of the Control group revealed that JTi/QRSi was not affected by age. The JTi/QRSi of the MCG is more sensitive to coronary stenosis than ECG, and this parameter improves soon after coronary revascularization.
    Circulation Journal 10/2007; 71(10):1586-92. · 3.58 Impact Factor
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    ABSTRACT: Regeneration of the lung microvasculature and replacing pulmonary artery lesions with functional endothelial cells could be a novel and effective therapeutic strategy for treating advanced pulmonary arterial hypertension (PAH). In the present study it was postulated that granulocyte colony-stimulating factor (G-CFS), which induces the proliferation of endothelial cells, would stimulate endothelial regeneration in situ at sites of impaired lung vasculature and prevent the development of PAH. Daily administration of G-CSF for 48 days did not affect the hemodynamism of normal Fischer 344 rats. PAH was induced with monocrotaline (60 mg/kg) and G-CSF was administered daily (100 microg/kg per day). Echocardiographic findings and an invasive catheter study indicated a significant decrease in the progression of PAH in rats given G-CSF. Furthermore, G-CSF increased Ki-67 positivity in the pulmonary arteries of PAH rats but did not accelerate c-kit positive cell recruitment into peripheral blood. Daily doses of G-CSF at both 2 and 100 microg/kg improved the survival and body weight gain of PAH rats. G-CSF improved the progression of PAH in a rat model, possibly by stimulating pulmonary endothelial cells to proliferate at sites of impaired lung vasculature. These findings show that cytokine therapy for PAH is valid based on the concept of vascular regeneration.
    Circulation Journal 02/2007; 71(1):138-43. · 3.58 Impact Factor
  • Journal of Cardiac Failure. 18(10):S137.