Mitsuru Ohishi

Osaka University, Suika, Ōsaka, Japan

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Publications (168)705.64 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine whether carrying out the Comprehensive Geriatric Assessment before operations would be useful for predicting complications, particularly postoperative delirium (POD), in old-old patients. A total of 517 patients aged 75 years and older, who underwent radical surgery for gastrointestinal cancer at Osaka University Hospital, were recruited for this observational study. The Comprehensive Geriatric Assessment components and assessment of performance status were carried out before surgery, and a record of postoperative complications including POD was made prospectively until discharge from hospital. The following morphological and clinical measurements were also obtained from the medical records: age, sex, disease type, previous history, comorbid lifestyle-related diseases, POD, postoperative complications, operative method, duration of operation, hemorrhage volume, blood transfusion volume, method of anesthesia, body mass index and blood tests. POD appeared in 24.0% of the 517 patients who underwent surgery. Barthel Index, Mini-Mental State Examination, instrumental activities of daily living and Geriatric Depression Scale results were associated with the incidence of POD, and the Barthel Index, Mini-Mental State Examination and Instrumental Activities of Daily Living results were extracted as independent factors associated with the development of POD after adjusting for traditional risk factors for postoperative complications and performance status. The Comprehensive Geriatric Assessment before gastrointestinal surgery can be a useful tool for predicting the development of POD in old-old patients. Geriatr Gerontol Int 2015; ●●: ●●-●●. © 2015 The Authors. Geriatrics & Gerontology International published by Wiley Publishing Asia Pty Ltd on behalf of Japan Geriatrics Society.
    No preview · Article · Aug 2015 · Geriatrics & Gerontology International
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    Dataset: pgs.13

    Full-text · Dataset · May 2015
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    ABSTRACT: The angiotensin II type 1 receptor (AT1) is a 7-transmembrane domain GPCR that when activated by its ligand angiotensin II, generates signaling events promoting vascular dysfunction and the development of cardiovascular disease. Here, we show that the single-transmembrane oxidized LDL (oxLDL) receptor (LOX-1) resides in close proximity to AT1 on cell-surface membranes and that binding of oxLDL to LOX-1 can allosterically activate AT1-dependent signaling events. oxLDL-induced signaling events in human vascular endothelial cells were abolished by knockdown of AT1 and inhibited by AT1 blockade (ARB). oxLDL increased cytosolic G protein by 350% in Chinese hamster ovary (CHO) cells with genetically induced expression of AT1 and LOX-1, whereas little increase was observed in CHO cells expressing only LOX-1. Immunoprecipitation and in situ proximity ligation assay (PLA) assays in CHO cells revealed the presence of cell-surface complexes involving LOX-1 and AT1. Chimeric analysis showed that oxLDL-induced AT1 signaling events are mediated via interactions between the intracellular domain of LOX-1 and AT1 that activate AT1. oxLDL-induced impairment of endothelium-dependent vascular relaxation of vascular ring from mouse thoracic aorta was abolished by ARB or genetic deletion of AT1. These findings reveal a novel pathway for AT1 activation and suggest a new mechanism whereby oxLDL may be promoting risk for cardiovascular disease.-Yamamoto, K., Kakino, A., Takeshita, H., Hayashi, N., Li, L., Nakano, A., Hanasaki-Yamamoto, H., Fujita, Y., Imaizumi, Y., Toyama-Yokoyama, S., Nakama, C., Kawai, T., Takeda, M., Hongyo, K., Oguro, R., Maekawa, Y., Itoh, N., Takami, Y., Onishi, M., Takeya, Y., Sugimoto, K., Kamide, K., Nakagami, H., Ohishi, M., Kurtz, T. W., Sawamura, T., Rakugi, H. Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin-like oxLDL receptor. © FASEB.
    No preview · Article · Apr 2015 · The FASEB Journal
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    Full-text · Dataset · May 2014
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    ABSTRACT: Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase activity and maintain extracellular matrix homeostasis. Although TIMP-3 has multiple functions (e.g., apoptosis, inhibition of VEGF binding to VEGF receptor, and inhibition of TNFα converting enzyme), its roles in thermogenesis and metabolism, which influence energy expenditure and can lead to the development of metabolic disorders when dysregulated, are poorly understood. This study aimed to determine whether TIMP-3 is implicated in metabolism by analyzing TIMP-3 knockout (KO) mice. TIMP-3 KO mice had higher body temperature, oxygen consumption, and carbon dioxide production than wild-type (WT) mice, although there were no differences in food intake and locomotor activity. These results suggest that metabolism is enhanced in TIMP-3 KO mice. Real-time PCR analysis showed that the expression of PPAR-δ, UCP-2, NRF-1 and NRF-2 in soleus muscle, and PGC-1α and UCP-2 in gastrocnemius muscle, was higher in TIMP-3 KO mice than in WT mice, suggesting that TIMP-3 deficiency may increase mitochondrial activity. When exposed to cold for 8 hours to induce thermogenesis, TIMP-3 KO mice had a higher body temperature than WT mice. In the treadmill test, oxygen consumption and carbon dioxide production were higher in TIMP-3 KO mice both before and after starting exercise, and the difference was more pronounced after starting exercise. Our findings suggest that TIMP-3 KO mice exhibit enhanced metabolism, as reflected by a higher body temperature than WT mice, possibly due to increased mitochondrial activity. Given that TIMP-3 deficiency increases energy expenditure, TIMP-3 may present a novel therapeutic target for preventing metabolic disorders.
    Full-text · Article · Apr 2014 · PLoS ONE
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    ABSTRACT: Many reports have shown that brachial-ankle pulse wave velocity (baPWV) and carotid-femoral PWV are prognostic factors for cardiovascular diseases. We evaluated heart-carotid PWV, heart-femoral PWV (hfPWV), and femoral-ankle PWV (faPWV) using carotid and femoral sensors. Our objectives were to reveal correlations among PWVs and to determine the clinical importance of the respective PWVs in predicting the cardiovascular events. This prospective cohort study included 338 patients with essential hypertension (mean age 61.3 ± 0.7, mean follow-up period 6.5 ± 0.1 years) whose regional PWVs were measured. Primary end points were stroke, cardiovascular diseases (CVD), and death. Kaplan-Meier analysis showed that subjects with higher faPWV and baPWV had a significantly higher incidence of stroke (p = 0.0288 and 0.0277, respectively), subjects with higher hfPWV had a significantly higher incidence of CVD (p = 0.0212), subjects with higher baPWV and hfPWV had a significantly higher incidence of stroke + CVD (p = 0.0070 and 0.0463, respectively), and subjects with higher baPWV had a significantly higher mortality rate (p = 0.0367). Cox proportional hazard model revealed that baPWV was a significant risk factor for stroke + CVD after adjustment for traditional risk factors (relative risk: 14.50, p = 0.0288). Higher baPWV may be a risk factor for stroke and CVD, but the prognostic impact of regional PWVs is still unclear in patients with hypertension.
    No preview · Article · Feb 2014 · Heart and Vessels
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    ABSTRACT: To determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular (CVD) events beyond conventional risk factors. Several studies have shown that aPWV may be a useful risk factor for predicting CVD but have been underpowered to examine whether this is true for different sub-groups. We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with cardiovascular outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects. Of 17,635 participants, 1,785 (10%) had a cardiovascular (CVD) event. The pooled age- and sex-adjusted hazard ratio [95% CI] per SD change in loge aPWV was 1.35 [1.22, 1.50, p<0.001] for coronary heart disease (CHD), 1.54 [1.34, 1.78, p<0.001] for stroke, and 1.45 [1.30, 1.61, p<0.001) for CVD. Associations stratified by sex, diabetes and hypertension were similar, but decreased with age (1.89, 1.77, 1.36 and 1.23 for ≤50, 51-60, 61-70 and >70 years respectively, pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor: CHD 1.23, [1.11, 1.35 p<0.001]; stroke 1.28, [1.16, 1.42 p<0.001]; cardiovascular events 1.30 [1.18, 1.43, p<0.001]. Reclassification indices showed the addition of aPWV improved risk prediction (13% for 10 year CVD risk for intermediate risk) for some sub-groups. Consideration of aPWV improves model fit and reclassifies risk for future cardiovascular events in models that include standard risk factors. aPWV may enable better identification of high-risk populations who may benefit from more aggressive cardiovascular risk factor management.
    Full-text · Article · Nov 2013 · Journal of the American College of Cardiology
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    ABSTRACT: Background: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). Methods: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. Results: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. Conclusion: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension.
    Full-text · Article · Nov 2013 · Pharmacogenomics

  • No preview · Article · Sep 2013 · European geriatric medicine
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    ABSTRACT: The mean intima media thickness (IMT) and plaque score from carotid ultrasonography are both widely used to evaluate macrovascular atherosclerotic change. The present study sought to examine which parameter more effectively predicts patient prognosis. This hospital-based cohort study included 356 patients with essential hypertension (mean age: 62.4±0.6). We investigated how the mean IMT and plaque score correlated with various parameters, including pulse wave velocity (PWV), and we assessed the ability of the mean IMT and plaque score to predict cardiovascular events and total mortality. The mean IMT and plaque score significantly correlated with systemic atherosclerotic change, target organ damage, age and PWV. Subjects with a higher mean IMT and subjects with higher plaque scores showed higher frequencies of stroke and total mortality. In addition, subjects with marginal thickening of the intima media (mean0.7) showed a significantly higher frequency of stroke than subjects with a mean IMT of <0.7. After adjustment for traditional risk factors, plaque score was significantly and independently predictive of stroke, and the predictive ability of the plaque score for the onset of stroke was equivalent to that of PWV. The mean IMT and plaque score showed a nonsignificant trend of higher risk of mortality after adjustment for traditional risk factors. The mean IMT and plaque score were significantly correlated with systemic atherosclerotic change. We revealed that plaque score predicted the onset of stroke more accurately than the mean IMT, and the accuracy of this prediction was equivalent to that from PWV in hypertensive patients. We also showed that marginal thickening of the intima media (as measured by mean IMT) may be a predictor of stroke.Hypertension Research advance online publication, 4 July 2013; doi:10.1038/hr.2013.61.
    No preview · Article · Jul 2013 · Hypertension Research
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    Koichi Yamamoto · Masao Takeda · Mitsuru Ohishi · Hiromi Rakugi

    Full-text · Article · Jul 2013 · Diabetes
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    ABSTRACT: To assess how visit-to-visit variability of SBP correlates with systemic atherosclerotic change and various prognoses. Visit-to-visit SBP variability correlates with cardiovascular events. However, the mechanisms underlying the impact of visit-to-visit SBP variability on prognoses are poorly understood. A total of 485 patients with essential hypertension from the Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) study cohort were included. We analyzed the correlation between visit-to-visit SBP variability and multiple clinical parameters. Next, we prospectively examined the correlation of SBP variability and frequency of cardiovascular disease (CVD) and total mortality. Patients with higher SBP variability exhibited significantly higher rates of statin use, as well as higher pulse wave velocity (PWV), left-ventricular mass index (LVMI), plaque score, and resistive index of the common carotid artery; these patients also exhibited lower estimated glomerular filtration rate. Kaplan-Meier analysis demonstrated that patients with higher SBP variability have a significantly higher incidence of CVD and mortality rate. The hazard ratio of SBP variability for incidence of CVD was greatly diminished after adjustment for intima-media thickness, plaque score, and resistive index, and was slightly diminished after adjustment for PWV and LVMI. Visit-to-visit SBP variability remained an independent risk factor for mortality after adjustment. Visit-to-visit SBP variability correlates significantly with systemic atherosclerotic change, incidence of CVD, and mortality rate. Altered arterial functions, such as macrovascular atherosclerosis and vascular resistance, are responsible for the correlations between visit-to-visit SBP variability and incidence of CVD.
    No preview · Article · Jul 2013 · Journal of Hypertension
  • Y. Takeya · M. Ohishi

    No preview · Article · Jun 2013 · Kokyu to junkan. Respiration & circulation
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    ABSTRACT: Fixed-dose combination (FDC) therapy with telmisartan 40 mg+amlodipine 5 mg (T40/A5) is expected to achieve tight blood pressure (BP) control because of the strong efficacy and long half-life of each drug. The aims of this study were to evaluate the 24-h antihypertensive efficacy of T40/A5 FDC therapy and to explore differences that may arise owing to different administration times in Japanese patients whose hypertension was not controlled by 5 mg of amlodipine per day. In this randomized clinical trial, 44 patients who had been taking amlodipine 5 mg per day and did not achieve their optimal BP target were enrolled (mean age: 67.8±10.2 years). The subjects were then randomly assigned to a T40/A5 morning or evening administration group (22 patients per group). At baseline and 8 weeks after randomization, we evaluated clinical BP and various laboratory values and performed ambulatory BP monitoring (ABPM). Clinical and mean BP evaluated with ABPM at 8 weeks (24 h, daytime, nighttime and early morning) were significantly decreased compared with BP at baseline. There were no significant differences in the diurnal BP profile change from baseline to 8 weeks between subjects in the morning and evening administration groups. There were also no significant differences in the diurnal BP profile change from baseline to 8 weeks between subjects with or without metabolic syndrome. We conclude that T40/A5 FDC therapy significantly decreased the 24-h mean and clinical BP, independent of administration time, in patients whose hypertension was not controlled by 5 mg of amlodipine.Hypertension Research advance online publication, 21 February 2013; doi:10.1038/hr.2013.10.
    Full-text · Article · Feb 2013 · Hypertension Research
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    ABSTRACT: Aim: Several studies using experimental non-alcoholic fatty liver disease (NAFLD) models have shown that ezetimibe, an inhibitor of cholesterol absorption mainly in the intestine, not only protects against diet-induced hyperlipidemia, but also attenuates liver steatosis. The aim of this study was to clarify whether ezetimibe inhibits the development of NAFLD and to elaborate the mechanism of ezetimibe to inhibit the development of NAFLD using Fatty Liver Shionogi (FLS) mice, a spontaneous model of NAFLD/non-alcoholic steatohepatitis. Methods: Male FLS mice at 20 weeks of age were divided into two groups (n = 7 in each group). Mice fed a normal laboratory chow, CRF-1 or CRF-1 containing 0.005% w/w ezetimibe (7 mg/kg per day) for 4 weeks. After 4-week treatment with ezetimibe, the livers of each group of mice were subjected to histological as well as molecular evaluation. Results: Ezetimibe administration for 4 weeks was associated with improvement of steatosis and fibrosis of the liver in normal diet-fed FLS mice. Ezetimibe reduced hepatic reactive oxygen species generation and prevented ubiquitination and protein degradation of microsomal triglyceride transfer protein (MTP), a key molecule for very low-density lipoprotein assembly and export, via downregulation of the protein expression of Skp2 and CDC20. Conclusion: Ezetimibe not only reduced lipid synthesis in the liver, but also promoted lipid discharge from the liver by preventing post-translational degradation of MTP via a reduction of hepatic reactive oxygen species generation, leading to inhibition of the development of NAFLD.
    Full-text · Article · Feb 2013 · Hepatology Research
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    Ada Congrains · Kei Kamide · Mitsuru Ohishi · Hiromi Rakugi
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    ABSTRACT: ANRIL is a recently discovered long non-coding RNA encoded in the chromosome 9p21 region. This locus is a hotspot for disease-associated polymorphisms, and it has been consistently associated with cardiovascular disease, and more recently with several cancers, diabetes, glaucoma, endometriosis among other conditions. ANRIL has been shown to regulate its neighbor tumor suppressors CDKN2A/B by epigenetic mechanisms and thereby regulate cell proliferation and senescence. However, the clear role of ANRIL in the pathogenesis of these conditions is yet to be understood. Here, we review the recent findings on ANRIL molecular characterization and function, with a particular focus on its implications in human disease.
    Full-text · Article · Jan 2013 · International Journal of Molecular Sciences
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    ABSTRACT: Several studies have revealed that lower hepatic expression of microsomal triglyceride transfer protein (MTP) plays an important role in the development of nonalcoholic steatohepatitis (NASH). The aim of this study was to clarify the relationship between MTP and apoptosis using Fatty Liver Shionogi mice (FLS). We checked the phenotypes including the degree of apoptosis and performed molecular biological examinations in 16- and 48-week-old FLS and C57BL/6J mice (B6). The influence of MTP induction on apoptosis was examined using vector-mediated hepatic expression of MTP. The degree of hepatic apoptosis indicated by TUNEL staining, the gene expression of Bax and Bcl-2 and the protein expression of Bax and cleaved caspase3 were markedly increased in 48-week-old FLS compared to 48-week-old B6. TUNEL-positive cells and the protein expression of Bax, Bcl-2 and cleaved caspase3 were markedly increased in 48-week-old FLS compared to 16-week-old FLS. Hepatocyte apoptosis was increased in 16-week-old FLS with increased TUNEL-positive cells and upregulation of the protein expression of Bax compared to those in 16-week-old B6. The pAKT/AKT ratio was decreased in 48-week-old FLS compared to 16-week-old FLS and 48-week-old B6. Hepatic induction of MTP resulted in not only amelioration of steatosis as well as insulin resistance, but also prevention of the progression to hepatic apoptosis via inhibition of the expression of Bax and cleaved caspase3 accompanied by restoration of the pAKT/AKT ratio. Our findings suggested that MTP might play a pivotal role in preventing the progression to hepatic apoptosis in the development of NASH via improvement of hepatic insulin resistance.
    No preview · Article · Jan 2013 · Immunology Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents)
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    ABSTRACT: Aim: Arterial stiffness has been reported to correlate with cardiovascular disease (CVD). Brachial-ankle pulse wave velocity (baPWV) is easy to measure and has been used as a marker to evaluate arterial stiffness. The objective of the present study was to determine the cut-off value of baPWV for predicting cardiovascular prognosis in a prospective cohort study. Methods: Four hundred forty patients with essential hypertension were analyzed in study 1 with a mean follow-up of 6.3±0.1 years. Four hundred patients from study 1 who did not have a past history of CVD and/or stroke were analyzed in study 2 with a mean follow-up of 6.4±0.1 years. Stroke, CVD, and death were the primary endpoints. Results: Receiver operating characteristic (ROC) curve analysis revealed that 1750.0 cm/sec is an appropriate cut-off value for baPWV to predict the onset of stroke, CVD, stroke+CVD, and total mortality (area under curve: 0.576-0.719). A baPWV higher than 1750.0 may also be a significant and independent risk factor for the onset of CVD+stroke (relative risk: 2.048 (1.176-3.616), p= 0.0113 in study 1; relative risk: 1.920 (1.028-3.634), p=0.0408 in study 2). Conclusions: The present study indicates that 1750.0 cm/sec could be a useful cut-off value for baPWV to predict cardiovascular prognosis.
    No preview · Article · Dec 2012 · Journal of atherosclerosis and thrombosis
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    ABSTRACT: The development of atherosclerosis is associated with disturbances in mitochondrial function that impair effective adenosine triphosphate (ATP) production, increase generation of superoxide and induce subsequent apoptosis in vascular smooth muscle cells (VSMCs). As peroxisome proliferator-activated receptor gamma (PPARγ) has a potentially important role in the regulation of mitochondrial metabolism, we studied effects of the partial PPARγ agonist and angiotensin receptor blocker telmisartan, on mitochondria-related cellular responses in VSMC. In human VSMC, telmisartan increased ATP levels and activation of mitochondrial complex II, succinate dehydrogenase, reduced the release of H(2)O(2) and attenuated H(2)O(2)-induced increases in caspase 3/7 activity, a marker of cellular apoptosis. Eprosartan, an angiotensin II receptor blocker that lacks the ability to activate PPARγ, had no effect on these mitochondria-related cellular responses in VSMC. Studies in PPARγ-deficient VSMC revealed that the effects of telmisartan on mitochondrial function were largely independent of PPARγ although the presence of PPARγ modulated effects of telmisartan on H(2)O(2) levels. These findings demonstrate that telmisartan can have significant effects on mitochondrial metabolism in VSMC that are potentially relevant to the pathogenesis of cardiovascular disease and that involve more than just angiotensin receptor blockade and activation of PPARγ.Hypertension Research advance online publication, 20 December 2012; doi:10.1038/hr.2012.199.
    Full-text · Article · Dec 2012 · Hypertension Research
  • Mitsuru Ohishi · Koichi Yamamoto · Hiromi Rakugi
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    ABSTRACT: In the classical renin angiotensin system (RAS), angiotensin II (Ang II) plays many important roles in cardiovascular disease and in kidney, brain, and other organs via the Ang II type 1 receptor (AT1). The RAS consists of many angiotensin peptides, including Ang (1-7), Ang (1-9), Ang (2-8), and Ang IV. Ang (1-7), produced by angiotensin-converting enzyme 2 (ACE2), has received attention because ACE2-deficient mice have heart failure. In addition, the proto-oncogene mas and insulin regulatory aminopeptidase (IRAP) have been identified as receptors for Ang (1-7) and Ang IV, respectively, accelerating investigations into both peptides. Many groups have suggested that the ACE2/Ang (1-7)/mas axis results in beneficial effects in cardiovascular disease, renal damage, and glucose intolerance and plays an independent role in kidney disease and glucose metabolism. On the other hand, Ang IV/IRAP strongly influences memory disturbance and protects against brain ischemia. Finally, the classical RASACE/Ang II/AT1 axis blockade yields beneficial effects in the context of organ damage, and additional modulation of ACE2/Ang (1-7)/mas or angiotensin IV/IRAP with this blockade results in even greater improvement. In the near future, new treatments targeting RAS and using new angiotensin peptide players might be developed for managing lifestyle-related disease.
    No preview · Article · Nov 2012 · Current pharmaceutical design

Publication Stats

4k Citations
705.64 Total Impact Points


  • 2003-2015
    • Osaka University
      • • Division of Geriatric Medicine and Nephrology
      • • Graduate School of Medicine
      Suika, Ōsaka, Japan
  • 2013-2014
    • Kagoshima University
      • Graduate School of Medical and Dental Sciences
      Kagosima, Kagoshima, Japan
  • 2002-2013
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 2010
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 1999-2002
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
  • 1996
    • Sakurabashi Watanabe Hospital
      Ōsaka, Ōsaka, Japan