Tetsuo Shioi

Kyoto University, Kioto, Kyōto, Japan

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Publications (95)613.02 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure (HF) is associated with changes in energy metabolism of the heart, as well as in extra-cardiac organs such as skeletal muscles. Cardiac cachexia is a common complication and is associated with a poor prognosis. Branched-chain amino acids (BCAA) reportedly improve sarcopenia and cancer cachexia. We tested the hypothesis that BCAA ameliorate HF with cardiac cachexia. We used Dahl salt-sensitive (DS) rats fed a high-salt diet as a model of HF. DS rats fed a low-salt diet were used as a control. BCAA were administered in drinking water from 11 weeks of age, when cardiac hypertrophy was established but the cardiac function was preserved. Survival and the cardiac function were monitored, and animals were sacrificed at 21 weeks of age and analyzed. In HF rats, BCAA treatment decreased the heart rate, preserved the cardiac function, and prolonged survival. BCAA also prevented body weight loss, associated with preservation of the skeletal muscle weight. Moreover, gene expression related to mitochondrial biogenesis and function was increased with BCAA in skeletal muscles. BCAA preserved the body weight and cardiac function and prolonged survival in HF rats. The expression of genes involved in mitochondrial biogenesis and function in skeletal muscles was increased by BCAA. Copyright © 2015. Published by Elsevier Inc.
    Life sciences 06/2015; 137. DOI:10.1016/j.lfs.2015.06.021 · 2.30 Impact Factor
  • International journal of cardiology 03/2015; 187:27-28. DOI:10.1016/j.ijcard.2015.03.354 · 6.18 Impact Factor
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    ABSTRACT: Many methods have been used to assess mitochondrial function. Technetium-99m sestamibi (99mTc-MIBI), a lipophilic cation, is rapidly incorporated into myocardial cells by diffusion and mainly localizes to the mitochondria. The purpose of this study was to investigate whether measurement of 99mTc-MIBI signals in animal models could be used as a tool to quantify mitochondrial membrane potential at the organ level. We analyzed 99mTc-MIBI signals in Sprague-Dawley (SD) rat hearts perfused with carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler known to reduce the mitochondrial membrane potential. 99mTc-MIBI signals could be used to detect changes in the mitochondrial membrane potential with sensitivity comparable to that obtained by two-photon laser microscopy with the cationic probe tetramethylrhodamine ethyl ester (TMRE). We also measured 99mTc-MIBI signals in the hearts of SD rats administered CCCP (4 mg/kg intraperitoneally) or vehicle. 99mTc-MIBI signals decreased in rat hearts administered CCCP, and the ATP content, as measured by 31P magnetic resonance spectroscopy, decreased simultaneously. Next, we administered 99mTc-MIBI to Dahl salt-sensitive rats fed a high-salt diet, which leads to hypertension and heart failure. The 99mTc-MIBI signal per heart tissue weight was inversely correlated with heart weight, cardiac function, and the expression of atrial natriuretic factor, a marker of heart failure, and positively correlated with the accumulation of labeled fatty acid analog. The 99mTc-MIBI signal per liver tissue weight was lower than that per heart tissue weight. Measurement of 99mTc-MIBI signals can be an effective tool for semiquantitative investigation of cardiac mitochondrial membrane potential in the SD rat model by using a chemical to decrease the mitochondrial membrane potential. The 99mTc-MIBI signal per heart tissue weight was inversely correlated with the severity of heart failure in the Dahl rat model.
    PLoS ONE 01/2015; 10(1):e0117091. DOI:10.1371/journal.pone.0117091 · 3.23 Impact Factor
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    ABSTRACT: Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrial-targeted nuclear genes in concert with reduced signaling via PPARα/PGC-1α and other transcriptional regulators. In cultured myocytes Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO, but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Molecular and Cellular Biology 12/2014; 35(5). DOI:10.1128/MCB.01109-14 · 5.04 Impact Factor
  • Takao Kato · Tetsuo Shioi · Akira Kawamoto · Takeshi Kimura
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    Journal of Cardiac Failure 10/2014; 20(10):S191. DOI:10.1016/j.cardfail.2014.07.329 · 3.07 Impact Factor
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    ABSTRACT: Previous studies reporting long-term (≥5 year) clinical outcome in patients with unprotected left main coronary artery (LMCA) disease undergoing drug-eluting stent (DES) implantation are currently limited, although late adverse events beyond 1 year are one of the major concerns of DES. We evaluated long-term clinical outcomes in 134 consecutive patients who underwent sirolimus-eluting stents (SES) for unprotected LMCA lesion in a single center from 2004 to 2009. The median follow-up duration was 3.8 (range: 0.5-7.9) years. Eight patients suffered from serious cardiovascular events potentially related to LMCA lesion (primary outcome measure) (sudden cardiac death: N = 5, emergent coronary revascularization for the LMCA lesion: N = 2, and acute congestive heart failure related to LMCA lesion: N = 1) with the cumulative 5-year incidence of only 4.4 %. The cumulative 5-year incidence of all-cause death, cardiac death, target vessel myocardial infarction, definite stent thrombosis, and target-lesion revascularization was 26.5, 8.1, 0, 0, and 12.9 %, respectively. In a subgroup analysis, the cumulative incidence of the primary outcome measure was significantly higher in patients with 2-stenting (N = 27) than in patients with 1-stenting (N = 107) (14.0 and 2.2 %, P < 0.001). All 8 patients with serious adverse events had a true bifurcation lesion and 5 patients received 2-stenting for the LMCA lesion. SES implantation in patients with unprotected LMCA lesion was associated with a favorable long-term outcome with acceptably low rate of serious adverse event potentially related to LMCA lesion. However, complex LMCA lesions necessitating 2-stenting strategy might be associated with higher risk for serious adverse events.
    Cardiovascular Intervention and Therapeutics 09/2014; 30(3). DOI:10.1007/s12928-014-0297-x
  • Takao Kato · Tetsuo Shioi · Takeshi Kimura
    Journal of Cardiac Failure 10/2013; 19(10):S144. DOI:10.1016/j.cardfail.2013.08.205 · 3.07 Impact Factor
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    ABSTRACT: Heart failure is associated with changes in cardiac energy metabolism. Glucose metabolism in particular is thought to be important in the pathogenesis of heart failure. We examined the effects of persistent overexpression of phosphoglycerate mutase 2 (Pgam2), a glycolytic enzyme, on cardiac energy metabolism and function. Transgenic mice constitutively overexpressing Pgam2 in a heart-specific manner were generated, and cardiac energy metabolism and function were analyzed. Cardiac function at rest was normal. The uptake of analogs of glucose or fatty acids and the phosphocreatine/βATP ratio at rest were normal. A comprehensive metabolomic analysis revealed an increase in the levels of a few metabolites immediately upstream and downstream of Pgam2 in the glycolytic pathway, whereas the levels of metabolites in the initial few steps of glycolysis and lactate remained unchanged. The levels of metabolites in the tricarboxylic acid (TCA) cycle were altered. The capacity for respiration by isolated mitochondria in vitro was decreased, and that for the generation of reactive oxygen species (ROS) in vitro was increased. Impaired cardiac function was observed in response to dobutamine. Mice developed systolic dysfunction upon pressure overload. Constitutive overexpression of Pgam2 modified energy metabolism and reduced stress resistance of heart in mice.
    PLoS ONE 08/2013; 8(8):e72173. DOI:10.1371/journal.pone.0072173 · 3.23 Impact Factor
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    ABSTRACT: OBJECTIVES: Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. METHODS AND RESULTS: In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53 downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. CONCLUSION: These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.
    Journal of Molecular and Cellular Cardiology 01/2013; 57(1). DOI:10.1016/j.yjmcc.2013.01.007 · 5.22 Impact Factor
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    ABSTRACT: Percutaneous transcatheter mitral valvuloplasty is the indicated treatment of choice for symptomatic native mitral valve stenosis, but there have been limited reports of successful procedures of balloon valvuloplasty for bioprosthetic mitral valve stenosis. We present the case of a 62-year-old woman suffering from progressive dyspnea due to bioprosthetic mitral valve stenosis. The measured mean pressure gradient across the mitral valve was 30 mmHg and the mitral valve area was 0.73 cm(2). Redoing mitral replacement was considered high risk and was refused by the patient. Percutaneous balloon valvuloplasty was performed with an Inoue balloon catheter inflated to 20 mm. The patient's symptoms immediately improved after the procedure, with no procedure-related complications. The mean pressure gradient across the valve decreased to 19 mmHg, and the mitral valve area increased to 1.21 cm(2) in postprocedural echocardiography. We conducted a literature search and identified 26 cases of balloon valvuloplasty for degenerated bioprosthetic valves. Of these, 14 cases were bioprosthetic mitral valves, and the results were favorable. However, more case reports are required to establish an evidence base for future expert recommendation of balloon valvuloplasty of prosthetic mitral valve. Meanwhile, balloon valvuloplasty will serve a niche role in highly selected patients with prosthetic mitral valve stenosis.
    Heart and Vessels 11/2012; 28(5). DOI:10.1007/s00380-012-0309-7 · 2.11 Impact Factor
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    Tetsuo Shioi · Yasutaka Inuzuka
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    ABSTRACT: Heart failure is a typical age-associated disease. However, the mechanism by which heart function declines and heart failure increases in association with age is not clear. Recent advances in basic science clarify several important mechanisms of aging. The mechanisms identified are likely to serve as substrates by which heart function declines and predisposes elderly people to heart failure. One such mechanism is insulin/insulin-like growth factor (IGF)-1 signaling. Suppression of insulin/IGF-1 signaling prevents cardiac aging associated with improved protein homeostasis in the heart. However, the role of insulin/IGF-1 signaling in heart diseases is likely to be pleiotropic, and both protective and sensitizing effects have been described in different contexts. Reduction in function of extra-cardiac organs is likely to be another important mechanism by which heart failure increases with aging, since heart failure is a multiple organ system disease.
    Journal of Cardiology 10/2012; 60(5-6). DOI:10.1016/j.jjcc.2012.07.015 · 2.57 Impact Factor
  • Journal of Cardiac Failure 10/2012; 18(10):S164. DOI:10.1016/j.cardfail.2012.08.211 · 3.07 Impact Factor
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    ABSTRACT: Conventional exercise training (ET) for elderly patients with heart failure (HF) includes low-intensity stretching and gait training. The effects of 2 types of low-intensity ET - machine-assisted cycling and conventional ET - on exercise capacity and endothelial function of elderly patients with HF was investigated in the present study. Twenty-seven elderly patients with HF (mean age: 79.5 years) were randomly assigned to either a machine-assisted cycling group or a conventional ET group. At baseline and after 2 weeks of ET, all patients were tested for 6-minute walk distance (6MWD) and digital reactive hyperemia-peripheral arterial tonometry (RH-PAT). After 2 weeks of ET, a significant increase in 6MWD was observed in both groups with no significant difference between the groups. RH-PAT index significantly increased in patients aged ≤80 (1.55±0.33 to 1.93±0.62, P=0.035) and a trend toward increase in RH-PAT index in the machine-assisted cycling group was observed (1.59±0.52 to 1.93±0.63, P=0.053), although no change was observed in the conventional ET group. In the multivariate model, patients' age and machine-assisted cycling were associated with the increases in RH-PAT index (P<0.05). Machine-assisted cycling appeared to be as effective as conventional ET on exercise capacity in elderly patients with HF. Additionally, machine-assisted cycling has the potential to improve endothelial function in these patients.
    Circulation Journal 05/2012; 76(8):1889-94. DOI:10.1253/circj.CJ-11-1113 · 3.69 Impact Factor
  • The American Journal of Cardiology 04/2012; 109(7):S132. DOI:10.1016/j.amjcard.2012.01.311 · 3.43 Impact Factor
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    ABSTRACT: Insulin/insulin-like growth factor-1 (IGF-1) signaling plays an important role in many biological processes. The class IA isoform of phosphoinositide 3-kinase (PI3K) is an important downstream effector of the insulin/IGF-1 signaling pathway. The aim of this study is to examine the effect of persistent activation of PI3K on gene expression and markers of cellular senescence in murine hearts. Transgenic mice expressing a constitutively active PI3K in a heart-specific manner were analyzed at the ages of 3 and 20 months. Effects of persistent activation of PI3K on gene expression were comprehensively analyzed using microarrays. Upon comprehensive gene expression profiling, the genes whose expression was increased included those for several heat shock chaperons. The amount and nuclear localization of a forkhead box O (FOXO) protein was increased. In addition, the gene expression of insulin receptor substrate-2 decreased, and that of phosphatase and tensin homolog deleted on chromosome ten (PTEN) increased, suggesting that the persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling. The expression of markers of cellular senescence, such as senescence-associated beta-galactosidase activity, cell cycle inhibitors, proinflammatory cytokines, and lipofuscin, did not differ between old wild-type and caPI3K mice. The persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling pathway in a transgenic mouse line. Markers of cellular senescence were not changed in the aged mutant mice.
    Life sciences 02/2012; 90(15-16):619-28. DOI:10.1016/j.lfs.2012.02.010 · 2.30 Impact Factor
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    ABSTRACT: Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD(+)-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.
    Journal of Molecular and Cellular Cardiology 09/2011; 51(6):1026-36. DOI:10.1016/j.yjmcc.2011.09.013 · 5.22 Impact Factor
  • Journal of Cardiac Failure 09/2011; 17(9). DOI:10.1016/j.cardfail.2011.06.591 · 3.07 Impact Factor
  • Journal of Cardiac Failure 09/2011; 17(9). DOI:10.1016/j.cardfail.2011.06.580 · 3.07 Impact Factor
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    ABSTRACT: BACKGROUND: Cachexia, namely body wasting, is a common complication in cases of congestive heart failure (CHF). Although, neurohumoral and immune abnormalities are associated with the condition, precisely how the imbalance of catabolism and anabolism is responsible for the wasting process is not known. METHODS: We analyzed markers of cachexia in Dahl salt-sensitive rats which show marked hypertension with preserved systolic function at 11weeks and CHF at 17-19weeks of age. We also analyzed the change in hepatic metabolism associated with CHF since liver plays a central role in the systemic regulation of catabolism and anabolism. RESULTS: In CHF rats, a failure to grow was observed and blood hepatic protein levels were decreased associated with increased blood proinflammatory cytokine levels, indicating that Dahl rats serve as a model of cardiac cachexia. Food intake was reduced, and blood sugar and insulin levels were decreased. Despite the apparent fasting condition, blood fatty acid levels were decreased and triglycerides levels were increased. In CHF rats, liver incorporated more glucose, the gene expression related to gluconeogenesis was decreased, the gene expression related to lipogenesis was increased, and the triglyceride content of the liver was increased. The paradoxical production of triglycerides synthesis in fasting rats was associated with a proinflammatory response in liver. CONCLUSIONS: The Dahl salt-sensitive rat can be used as a model of cardiac cachexia. The cachexia was associated with abnormal hepatic metabolism that might work as a maladaptive response during the progression of CHF.
    International journal of cardiology 08/2011; 161(3). DOI:10.1016/j.ijcard.2011.07.056 · 6.18 Impact Factor

Publication Stats

5k Citations
613.02 Total Impact Points


  • 1994–2015
    • Kyoto University
      • Department of Cardiovascular Medicine
      Kioto, Kyōto, Japan
  • 2010
    • Keio University
      • Institute for Advanced Biosciences
      Edo, Tōkyō, Japan
  • 2008–2010
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1999–2009
    • Beth Israel Deaconess Medical Center
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2004–2007
    • Kitasato University
      • Medical Department
      Edo, Tōkyō, Japan
  • 2000–2003
    • Harvard Medical School
      Boston, Massachusetts, United States