Hiroaki Matsubara

Kyoto Prefectural University of Medicine, Kioto, Kyōto, Japan

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Publications (359)1645.88 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: A 62-year-old female was admitted to our hospital for investigation of acute progressive renal insufficiency and a systemic inflammatory reaction, despite treatment with several antibiotics. Laboratory data revealed severe renal insufficiency and positive titers for the myeloperoxidase anti-neutrophil cytoplasmic and anti-glomerular basement membrane antibodies. The deterioration of her general status did not allow us to perform the renal biopsy. Although corticosteroid therapy, hemodialysis, and plasma exchange were concomitantly initiated, pulmonary hemorrhage occurred several days after admission. Mechanical ventilation support was provided and continuous hemodiafiltration was carried out, following which the respiratory failure improved immediately. However, she developed clinical depression and suicidal behavior under the intensive therapy. Therefore, plasma exchange was discontinued and corticosteroid was tapered as quickly as possible. Four months after admission, platelet transfusion and short-term mechanical ventilation support improved the pulmonary hemorrhage; however, her mental status deteriorated despite psychiatric consultation and treatment with a tranquilizer. Thereafter, severe and serious systemic infection due to various pathogens including Staphylococcus aureus, Cytomegalovirus, Pneumocystis jiroveci, Pseudomonas aeruginosa, and Bacteroides recurred, and she died from systemic invasive aspergillosis (IA). We suspected severe immunosuppression caused by various factors, such as predonisolone administration, chronic renal failure on maintenance hemodialysis, depression, and malnutrition due to chronic inflammation and granulocytopenia as a side effect of ganciclovir. When treating rapidly progressive glomerulonephritis, immunosuppressive status should be carefully monitored regarding not only the dosage of therapeutic regimen but also the mental health status and nutrition of the patient.
    Clinical nephrology 04/2011; 75(4):384-8. DOI:10.2379/CNX06358 · 1.23 Impact Factor
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    ABSTRACT: A decreased plasma level of vitamin C has been reported to be associated with an increased risk of cardiovascular morbidity and mortality. Here, we sought to determine the vitamin C status of patients with chronic kidney disease and the pathophysiological role of vitamin C in these patients. We studied 58 patients and evaluated the relationship between renal function and plasma vitamin C concentration, as well as the effect of diabetes on this relationship. Endothelium-dependent flow-mediated dilation of brachial artery was measured to assess the endothelial function. Serum malondialdehyde low-density lipoprotein was measured as a marker for oxidative stress. Plasma vitamin C concentration had a positive linear relationship with eGFR in both diabetic and non-diabetic patients (P = 0.006 and P = 0.004, respectively). When vitamin C concentration and eGFR relationships were compared in the two groups, vitamin C concentration was significantly lower in diabetic patients at every eGFR (P = 0.006). Flow-mediated vasodilatation of the brachial artery was positively correlated with vitamin C concentration in non-diabetic patients (P = 0.047) but not in diabetic patients. There was a negative correlation between serum malondialdehyde low-density lipoprotein and vitamin C concentration in non-diabetic patients (P = 0.044) but not in diabetic patients. Renal dysfunction was associated with a decrease in plasma vitamin C level. Moreover, decreased vitamin C may cause endothelial dysfunction via an increase in oxidative stress in non-diabetic chronic kidney disease patients.
    Nephrology Dialysis Transplantation 04/2011; 26(4):1252-7. DOI:10.1093/ndt/gfq547 · 3.49 Impact Factor
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    ABSTRACT: Research in 2008 demonstrated that the majority of out-of-hospital cardiac arrests (OHCAs) occur in the home, and many important characteristics differ between private and public locations. However, the influence of the location of collapse on survival from OHCA is not well understood. Furthermore, most of the reports have been from Western countries; there is little research from Asia that differentiates the conditions of OHCA. To investigate the influence of the location of collapse on being discharged alive from OHCA and whether the location of collapse is also an independent predictor of survival from OHCA in Japan. We analyzed 463 consecutive cases of witnessed OHCA with cardiac etiology that occurred between October 2004 and September 2008 in Japan. We investigated the characteristics of OHCA patients who collapsed in private and public locations, and assessed the influence of the location of collapse on survival from OHCA. Patients who collapsed outside the home were younger, more likely to be male, more likely to receive bystander cardiopulmonary resuscitation (CPR), and more likely to have ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) and had a shorter time interval between collapse and 9-1-1 call than patients who collapsed in the home. Mortality was significantly higher in the group who collapsed in the home. The independent influence of the location of collapse was eliminated by additional adjustment for time interval from collapse to 9-1-1 call, age, bystander CPR, and initial cardiac rhythm. Finally, VF/pulseless VT as the initial rhythm and bystander CPR were independently associated with the patient's being discharged alive; the location of collapse was not an independently associated variable. The present analysis demonstrated that there were significant differences in survival between groups of patients who suffered from cardiac arrest inside and outside the home in Japan. The outside-the-home group had a higher rate of survival from OHCA; however, the location of collapse was not an independent predictor of survival from OHCA. Education of the families of high-risk patients in placing a rapid emergency call and performing effective CPR might be needed to improve survival from cardiac arrest in the home.
    Prehospital Emergency Care 03/2011; 15(2):271-7. DOI:10.3109/10903127.2010.545475 · 1.81 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) are involved in the initial process of atherosclerosis, whereas it remains to be determined how atherogenic stimulus causes ROS-mediated proinflammatory reactions. Here, we focused on proline-rich tyrosine kinase (PYK2)-mediated ROS generation and examined how atherogenic stimulus causes early proinflammatory reactions. PYK2-deficient (knockout [KO]) (PYK2-KO) mice were crossbred with apolipoprotein E (ApoE)-deficient (PYK2-KO/ApoE-KO) mice. PYK2-KO/ApoE-KO mice and endothelial cells (EC) were used for the study. Aortic atherogenic lesions in PYK2-KO/ApoE-KO mice were markedly decreased (55% versus ApoE-KO) after 8 weeks of a Western diet. Aortic PYK2 was activated as early as 7 days after the Western diet, when inflammatory cells were not yet activated. Addition of the proatherogenic oxidized phospholipid lysophosphatidylcholine caused activation of endothelial PYK2. Lysophosphatidylcholine-activated PYK2 induced NADPH oxidase-mediated ROS generation and ROS-mediated synthesis of tumor necrosis factor-α (TNFα), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and p21Cip1/Ets-1. Neutralizing anti-TNFα antibody or knockdown of p21Cip1/Ets-1 system blocked the induction of VCAM-1 and MCP-1. PYK2 deficiency abolished these ROS-mediated proinflammatory reactions. Further analysis revealed that PYK2/ROS-mediated p21Cip1/Ets-1 activation upregulated the transcription of the MCP-1 gene in collaboration with p300 transcription coactivator. PYK2 is a key tyrosine kinase activated by high cholesterol exposure, which causes ROS-mediated TNFα release and induces TNFα-dependent expression of proinflammatory molecules via the p21Cip1/Ets-1/p300 transcription system.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2011; 31(5):1084-92. DOI:10.1161/ATVBAHA.110.221804 · 5.53 Impact Factor
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    ABSTRACT: The objective of the present study was to examine whether baseline electrocardiographically diagnosed left ventricular hypertrophy (ECG-LVH) influenced the angiotensin II receptor blocker (ARB) valsartan add-on effects on the cardio-cerebrovascular morbidity and mortality in the high-risk hypertensive patients who participated in the KYOTO HEART Study. The primary endpoint was the same as in the main study: a composite of defined cardiovascular and cerebrovascular events. The median follow-up period was 3.27 years. The study group was divided into 2 groups according to the presence of ECG-LVH: with LVH, n=803; without LVH, n=2,228. The primary endpoint events occurred more frequently in patients with LVH than in patients without LVH (9.3% vs. 7.3%; hazard ratio [HR], 1.33; 95% confidence interval [CI]: 1.01-1.75). Valsartan add-on significantly decreased the occurrence of primary endpoint events in both LVH-positive patients (5.8% vs. 12.9%; HR, 0.45; 95%CI: 0.28-0.72) and LVH-negative patients (5.5% vs. 9.2%; HR, 0.59; 95%CI: 0.44-0.81) compared with non-ARB treatment. The reduction in combined cardiovascular events (composite of acute myocardial infarction, angina pectoris, and heart failure) due to valsartan treatment in patients with LVH was significantly larger than that in patients without LVH (P<0.0001). Changes in blood pressure during the follow-up period did not differ significantly among the study subgroups. High-risk hypertensive patients with ECG-LVH might gain more cardiovascular benefits from valsartan add-on treatment, compared with patients without ECG-LVH.
    Circulation Journal 03/2011; 75(4):806-14. DOI:10.1253/circj.CJ-11-0059 · 3.69 Impact Factor
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    ABSTRACT: In this study, we report the comparative result of long-term clinical prognoses for patients with no-option critical limb ischemia (CLI) caused by arteriosclerosis obliterans, who are implanted with autologous bone marrow mononuclear cells (BMMNC; n=74) or G-CSF-mobilized (M)-PBMNC (n=111), as no information is available on how the two treatments compare in terms of long-term prognosis, such as survival or amputation. We performed pooled analysis using data from two previous cohort studies. All patients had disease of Fontaine classification III or IV. The endpoints were OS and amputation-free survival (AFS). After adjustment for history of dialysis and Fontaine classification, there was no significant difference between the two treatments with respect to OS (hazard ratio (HR)=1.49; 95% confidence interval (CI)=0.74-3.03, P=0.26) or AFS (HR=0.96; 95% CI=0.61-1.51, P=0.87). The negative prognostic factors affecting OS or AFS were the small number of CD34-positive cells collected, history of dialysis, Fontaine classification, male sex and older age. These results suggest that there was no significant difference in long-term prognosis between patients treated with BMMNC and those treated with M-PBMNC. The number of CD34-positive cells collected was an important prognostic factor for amputation and death.
    Bone marrow transplantation 02/2011; 46(2):278-84. DOI:10.1038/bmt.2010.110 · 3.47 Impact Factor
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    ABSTRACT: S100A12 is an endogenous receptor ligand for advanced glycation end products. Cardiovascular disease remains a major cause of morbidity and mortality in patients with chronic kidney disease. In this study, we report cross-sectional data on 550 hemodialysis patients and assess the relationship between plasma S100A12 level and cardiovascular disease. Design, SETTING, PARTICIPANTS, & MEASUREMENTS: A cross-sectional study of 550 maintenance hemodialysis patients was conducted. We investigated the past history of cardiovascular disease and quantified the plasma level of S100A12 protein in all participants. Plasma S100A12 level was higher in hemodialysis patients with cardiovascular disease (n=197; 33.8 ± 28.1 ng/ml) than in those without it (n=353; 20.2 ± 16.1 ng/ml; P<0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13 to 1.44; P<0.001) was identified as an independent factor associated with the prevalence of cardiovascular disease. The other factors associated with the prevalence of cardiovascular diseases were the presence of diabetes mellitus (OR, 2.81; 95% CI, 1.79 to 4.41; P < 0.001) and high-sensitivity CRP level (OR, 1.02; 95% CI, 1.00 to 1.05; P=0.046). Furthermore, the plasma S100A12 level (OR, 1.30; 95% CI, 1.09 to 1.54; P=0.004) was significantly associated with cardiovascular disease even in hemodialysis patients without diabetes mellitus (n=348). These results suggest that the plasma S100A12 protein level is strongly associated with the prevalence of cardiovascular disease in hemodialysis patients.
    Clinical Journal of the American Society of Nephrology 02/2011; 6(4):718-23. DOI:10.2215/CJN.08310910 · 5.25 Impact Factor
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    ABSTRACT: A necropsy study of patients with hypertrophic cardiomyopathy (HCM) who died at a young age exhibited marked disarray and fibrosis in the mid-wall layer of the left ventricular (LV) myocardium. We assessed ultrasonic tissue characteristics in the three layers of the ventricular septum (VS), and correlated the result with long-term prognosis in HCM. The magnitude of cyclic variation of integrated backscatter (CV-IB) was calculated in the three layers of the VS and the whole aspect of the LV posterior wall in 58 non-obstructive HCM patients and 20 healthy controls. All HCM patients were prospectively followed for an average period of 7.1 years for the occurrence of cardiac death or hospitalization due to heart failure. Each CV-IB of four regions was lower in HCM patients than in controls (all P < 0.01). CV-IB of the VS mid-wall layer was lower in 14 HCM patients with cardiac events than in patients without (5.4 ± 0.6 vs. 7.4 ± 0.5 dB, P = 0.033) although CV-IB of three other regions did not differ between the two groups. The optical cut-off point of %CV-IB <90%, i.e. the ratio of CV-IB in the VS mid-wall layer to the mean value in the layers on both sides, was an independent predictor of cardiac events (hazard ratio, 6.12; 95% confidence interval, 1.62-66.6; P = 0.013), with a positive predictive value of 44% and particularly with a high negative predictive value of 91%. Patients with non-obstructive HCM are not likely to undergo cardiac events in the near future, when the CV-IB value is not significantly lower in the VS mid-wall layer than in the layers on both sides.
    European Heart Journal – Cardiovascular Imaging 02/2011; 12(2):90-7. DOI:10.1093/ejechocard/jeq108 · 2.65 Impact Factor
  • Makoto Ariyoshi, Jun Shiraishi, Hiroaki Matsubara
    Internal Medicine 01/2011; 50(19):2237-8. DOI:10.2169/internalmedicine.50.6008 · 0.97 Impact Factor
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    ABSTRACT: Primary percutaneous coronary intervention (PCI) for ST-elevated myocardial infarction (STEMI) results in dramatically improved clinical outcomes when performed in a timely manner. Although guidelines for STEMI patients recommend PCI should be performed by experienced operators with acceptable PCI volume, cardiologists in a local area must perform primary PCI at their own hospitals. This study evaluated the effects of cardiologist experience on outcomes for STEMI patients in a local area in Japan.Between April 2007 and March 2010, 140 consecutive STEMI patients were admitted to our hospital and 121 of these patients received primary PCI. STEMI patients undergoing primary PCI were divided into two groups according to the operator's experience as a cardiologist. We retrospectively analyzed their clinical backgrounds, PCI findings, in-hospital outcomes, and drug administration at discharge.There were no significant differences in any clinical characteristics, angiographic findings, or PCI procedures between the two groups. Clinical outcomes of the two groups were similar, except for the length of hospital stay (21.1 ± 5.8 versus 15.5 ± 9.7; P = 0.0255). The frequency of administration of drugs such as β-blockers (59.1% versus 34.0%; P = 0.0086), aldosterone blockade (10.4% versus 25.5%; P = 0.0334), and nicorandil (76.1% versus 25.5%; P = < 0.0001) was different between the two groups.The clinical outcomes of STEMI patients in this study were satisfactory and almost equivalent when compared according to the experience of the attending cardiologist. The present findings suggest the important clinical implication that younger cardiologists who have experienced PCI procedures to a certain extent can safely perform primary PCI and contribute to better prognoses of STEMI patients.
    International Heart Journal 01/2011; 52(3):127-30. DOI:10.1536/ihj.52.127 · 1.13 Impact Factor
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    ABSTRACT: S100A12 is an endogenous ligand of the receptor for advanced glycation end products (RAGE). Plasma S100A12 levels are high in end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (HD). Peripheral arterial disease (PAD) is common in HD patients and is associated with increased cardiovascular morbidity and mortality rates in this population. To date, however, no study has specifically assessed the relationship between plasma S100A12 and PAD in HD patients. We conducted a cross-sectional study of 152 HD patients in our affiliated hospital. We investigated PAD history and patient characteristics and quantified plasma S100A12 levels in all participants. HD patients with PAD (n = 26; 21.9 [13.6-33.4] ng/ml) showed significantly higher plasma S100A12 levels than HD patients without PAD (n = 126; 11.8 [7.5-17.6]ng/ml; p < 0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR] 5.71; 95% confidence interval [CI] 1.29-25.3; p = 0.022) was identified as an independent factor associated with PAD prevalence. Another factor associated with PAD prevalence was the ankle-brachial index (OR 0.54; 95% CI 0.40-0.74; p < 0.001). These results suggest that plasma S100A12 levels are strongly associated with PAD prevalence in ESRD patients undergoing HD.
    01/2011; 1(1):242-50. DOI:10.1159/000335198
  • Journal of Arrhythmia 01/2011; 27(Supplement):OP14_2. DOI:10.4020/jhrs.27.OP14_2
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    D G A Burton, H Matsubara, K Ikeda
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    ABSTRACT: The accumulation of senescent cells within tissues can potentially lead to biological dysfunction and manifestation of disease associated with ageing. The majority of senescent cells display a commonly altered secretome similar to a wound healing response (termed the senescence-associated secretory phenotype or SASP), which could have deleterious implications on the tissue microenvironment. However, senescent cells also appear to have a cell-type (or even cell-strain) exclusive senescent phenotype (CESP), an area of research that is underexplored. One such CESP is the pro-calcificatory phenotype recently reported in senescent vascular smooth muscle cells (VSMCs). Senescent VSMCs have been shown to overexpress genes and proteins (including RUNX-2, alkaline phosphatase (ALP), type I collagen and BMP-2) associated with osteoblasts, leading to partial osteoblastic transdifferentiation. As such, it has been suggested that senescent VSMCs contribute to cardiovascular dysfunction through induction of vascular calcification. This review discusses recent findings on VSMC senescence and their potential role in the pathophysiology of vascular calcification.
    Experimental gerontology 11/2010; 45(11):819-24. DOI:10.1016/j.exger.2010.07.005 · 3.53 Impact Factor
  • Atsushi Hoshino, Takeshi Nakamura, Hiroaki Matsubara
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    ABSTRACT: Chronotherapy has the potential to improve blood pressure (BP) variability and to decrease stroke and cardiovascular events. The present study examined the efficacy and safety of the bedtime administration in amlodipine-olmesartan combination therapy, as compared with the morning administration. The present study was an open-label, randomized crossover study of the effects of the morning vs. bedtime administration of amlodipine-olmesartan combination. The subject was 31 essential hypertensive patients. Morning BP surge (MBPS) and nocturnal BP pattern were analyzed from ambulatory BP data. Glucose and lipid profiles and cardiovascular-renal data were also collected. The bedtime administration reduced MBPS significantly (24.2 ± 13.5 mmHg vs. 32.3 ± 14.2 mmHg, p < 0.001) with no excessive nocturnal BP fall. In nondipper, the bedtime administration significantly improved nocturnal BP. On the other hand, it did not reduce nocturnal BP in dipper. Urinary albumin/creatinine ratio was lower in the bedtime administration than in the morning administration (42.5 ± 59.9 mg/g vs. 75.3 ± 26.4 mg/g, p = 0.044). In amlodipine-olmesartan combination therapy, the bedtime administration reduced better MBPS with correcting nocturnal BP fall and improved urinary albumin excretion. The bedtime dosing of amlodipine and olmesartan seems more apt than the morning dose to obtain the therapeutic goal.
    Clinical and Experimental Hypertension 11/2010; 32(7):416-22. DOI:10.3109/10641961003667948 · 1.46 Impact Factor
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    ABSTRACT: Erythropoietin (EPO) enhances re-endothelialization and anti-apoptotic action. Larger clinical studies to examine the effects of high-dose EPO are in progress in patients with acute myocardial infarction (AMI). The aim of this multi-center pilot study was to investigate the effect of `low-dose EPO' (6,000 IU during percutaneous coronary intervention (PCI), 24 h and 48 h) in 35 patients with a first ST-elevated AMI undergoing PCI who was randomly assigned to EPO or placebo (saline) treatment. Neointimal volume, cardiac function and infarct size were examined in the acute phase and 6 months later (ClinicalTrials.gov identifier: NCT00423020). No significant regression in in-stent neointimal volume was observed, whereas left ventricular (LV) ejection fraction was significantly improved (49.2% to 55.7%, P=0.003) and LV end-systolic volume was decreased in the EPO group (47.7 ml to 39.0 ml, P=0.036). LV end-diastolic volume tended to be reduced from 90.2% to 84.5% (P=0.159), whereas in the control group it was inversely increased (91.7% to 93.7%, P=0.385). Infarction sizes were significantly reduced by 38.5% (P=0.003) but not in the control group (23.7%, P=0.051). Hemoglobin, peak creatine kinase values, and CD34(+)/CD133(+)/CD45(dim) endothelial progenitors showed no significant changes. No adverse events were observed during study periods. This is a first study demonstrating that short-term `low-dose' EPO to PCI-treated AMI patients did not prevent neointimal hyperplasia but rather improved cardiac function and infarct size without any clinical adverse effects.
    Circulation Journal 11/2010; 74(11):2365-71. DOI:10.1253/circj.CJ-10-0267 · 3.69 Impact Factor
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    ABSTRACT: Experience of primary percutaneous coronary intervention (PCI) for young adults with acute myocardial infarction (AMI) due to sequelae of Kawasaki disease (KD) has been extremely limited. In the present report on three young adults (two males and one female; age 20-35 years) with AMI, we performed primary PCI and intravascular ultrasound imaging (IVUS). Case 1 underwent thrombectomy alone in the proximal left circumflex coronary artery, and subsequent IVUS depicted a large aneurysm with an asymmetrically intimal thickening and a residual thrombus in the culprit. Case 2 underwent balloon dilation with adjunctive intracoronary thrombolysis in the proximal left anterior descending coronary artery (LAD), and IVUS during follow-up coronary angiography (CAG) delineated a regressed giant aneurysm with a markedly intimal thickening in the culprit. Case 3, with past history highly suggesting KD, underwent balloon dilation in the proximal LAD, and follow-up CAG as well as IVUS revealed a neoaneurysmal formation in the culprit. In all of the patients, PCI was angiographically effective at the acute phase without complication. Follow-up CAG performed 3-6 months after the procedure revealed no restenosis in all three cases, but a new coronary aneurysm still remained in case 3. Although case 1 and case 2 had no obvious history of KD, the vessel wall morphology from IVUS closely resembled the coronary sequelae after KD, suggesting that they might have antecedent incomplete KD. These cases suggest that primary PCI against coronary sequelae of KD in young AMI patients might be safe and effective in the short term.
    Heart and Vessels 11/2010; 26(1):117-24. DOI:10.1007/s00380-010-0051-y · 2.11 Impact Factor
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    ABSTRACT: Bioenergetic homeostasis is altered in heart failure and may play an important role in pathogenesis. p53 has been implicated in heart failure, and although its role in regulating tumorigenesis is well characterized, its activities on cellular metabolism are just beginning to be understood. We investigated the role of p53 and its transcriptional target gene TP53-induced glycolysis and apoptosis regulator (TIGAR) in myocardial energy metabolism under conditions simulating ischemia that can lead to heart failure. Expression of p53 and TIGAR was markedly upregulated after myocardial infarction, and apoptotic myocytes were decreased by 42% in p53-deficient mouse hearts compared with those in wild-type mice. To examine the effect of p53 on energy metabolism, cardiac myocytes were exposed to hypoxia. Hypoxia induced p53 and TIGAR expression in a p53-dependent manner. Knockdown of p53 or TIGAR increased glycolysis with elevated fructose-2,6-bisphosphate levels and reduced myocyte apoptosis. Hypoxic stress decreased phosphocreatine content and the mitochondrial membrane potential of myocytes without changes in ATP content, the effects of which were prevented by the knockdown of TIGAR. Inhibition of glycolysis by 2-deoxyglucose blocked these bioenergetic effects and TIGAR siRNA-mediated prevention of apoptosis, and, in contrast, overexpression of TIGAR reduced glucose utilization and increased apoptosis. Our data demonstrate that p53 and TIGAR inhibit glycolysis in hypoxic myocytes and that inhibition of glycolysis is closely involved in apoptosis, suggesting that p53 and TIGAR are significant mediators of cellular energy homeostasis and cell death under ischemic stress.
    AJP Heart and Circulatory Physiology 10/2010; 299(6):H1908-16. DOI:10.1152/ajpheart.00250.2010 · 4.01 Impact Factor
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    Journal of Cardiology Cases 10/2010; 2(2). DOI:10.1016/j.jccase.2010.03.001
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    ABSTRACT: Members of the fibroblast growth factor (FGF) family have been clinically applied to the treatment of ischemic diseases because of their strong angiogenic actions. Although tissue ischemia is predominantly caused by atherosclerosis, the roles of endothelial FGF receptors (FGF-Rs) in atherosclerosis remain obscure. We generated endothelial cell (EC)-targeted constitutively active FGF-R2-overexpressing mice, using the Tie2 promoter (Tie2-FGF-R2-Tg), and crossed them with apolipoprotein E (ApoE)-deficient mice (ApoE-KO) to generate Tie2-FGF-R2-Tg/ApoE-deficient mice (Tie2-FGF-R2-Tg/ApoE-KO). After being fed a Western diet for 8 wk, the Tie2-FGF-R2-Tg/ApoE-KO demonstrated 2.0-fold greater atherosclerotic lesion area on the luminal surfaces of the aortas than the ApoE-KO (P < 0.01). The level of p21(Cip1) protein, a cell cycle inhibitor, in the FGF-R2-overexpressing EC was 2.5-fold greater than that in the wild-type (WT) EC at the baseline (P < 0.01). FGF-R2 overexpression in the EC resulted in increased expression of VCAM-1 and ICAM-1, acceleration of apoptosis, and decreased proliferative activity, all of which were normalized by small interfering RNA (siRNA)-mediated knockdown of p21(Cip1) (75% reduction in protein level, P < 0.01). Furthermore, the expression of PDGF-B and Egr-1, a PDGF/p21(Cip1)-inducible transcription factor, in the aortic endothelium of Tie2-FGF-R2-Tg/ApoE-KO was significantly greater than that in ApoE-KO. The proliferation of vascular smooth muscle cells in the aortic media of Tie2-FGF-R2-Tg/ApoE-KO was 2.0-fold higher than that in ApoE-KO (P < 0.01). Thus our study reveals that endothelial FGF-R2 signaling aggravates atherosclerosis by promoting p21(Cip1)-mediated EC dysfunction and cautions against the use of FGF for therapeutic angiogenesis in the setting of atherosclerosis.
    AJP Heart and Circulatory Physiology 10/2010; 300(1):H154-61. DOI:10.1152/ajpheart.00075.2010 · 4.01 Impact Factor
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    ABSTRACT: Vascular calcification is an important risk factor for cardiovascular diseases. Here, we investigated a role of dedifferentiated vascular smooth muscle cells (VSMCs) in the atherosclerotic intimal calcification. We prepared human cultured VSMCs in either redifferentiatiated or dedifferentiated state and analyzed the gene expressions of bone-calcification regulatory factors. Expression of bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblast differentiation, was significantly enhanced in dedifferentiated VSMCs. Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs. Conditioned medium from dedifferentiated VSMCs, but not from redifferentiated VSMCs, stimulated the osteoblastic differentiation of the mesenchymal progenitor C2C12 cells, which was abolished by BMP-2 knockdown. In atherosclerotic intima from apolipoprotein (apo)E-deficient mice, αSM-actin-positive cells, presumably dedifferentiated VSMCs, expressed BMP-2. We generated BMP-2-transgenic mice using αSM-actin promoter and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout). Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice. Our findings collectively demonstrate an important role of dedifferentiated VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2010; 30(10):1908-15. DOI:10.1161/ATVBAHA.110.206185 · 5.53 Impact Factor

Publication Stats

10k Citations
1,645.88 Total Impact Points

Institutions

  • 2004–2013
    • Kyoto Prefectural University of Medicine
      • • Department of Cardiovascular Medicine
      • • Division of Cardiology and Vascular Regenerative Medicine
      Kioto, Kyōto, Japan
    • Kyoto Prefectural University
      Kioto, Kyōto, Japan
  • 2012
    • Nagoya Second Red Cross Hospital
      Nagoya, Aichi, Japan
  • 2011
    • Nikko Memorial Hospital
      Hidachi, Ibaraki, Japan
    • Asahikawa Medical University
      Asakhigava, Hokkaidō, Japan
  • 2010
    • Kyoto Pharmaceutical University
      • Division of Pathological Sciences
      Kioto, Kyōto, Japan
    • National Cerebral and Cardiovascular Center
      • Department of Cardiovascular Medicine
      Ōsaka, Ōsaka, Japan
    • Sakurakai Takahashi Hospital
      Kōbe, Hyōgo, Japan
  • 2007–2010
    • Kyoto Daini Red Cross Hospital
      Kioto, Kyōto, Japan
    • Kyoto University
      Kioto, Kyōto, Japan
  • 2006
    • Okayama University of Science
      • Department of Life Science
      Okayama, Okayama, Japan
  • 1987–2006
    • Kansai Medical University
      • • Second Department of Internal Medicine
      • • Cardiovascular Center
      • • Medical School
      Moriguchi, Ōsaka, Japan
  • 2003–2004
    • Asahi University
      Gihu, Gifu, Japan
  • 2001
    • Hiroshima University
      • Faculty of Medicine
      Hiroshima-shi, Hiroshima-ken, Japan
  • 1998
    • Harvard Medical School
      Boston, Massachusetts, United States