Bio

Honors & Awards


  • Research Fellowship, Uehara Memorial Foundation (2016)
  • International Scholarships, Banyu Life Science Foundation (2014-2015)
  • JSPS Fellow (DC2, PD), Japan Society for the Promotion of Science (2012-2013)

Professional Education


  • Doctor of Philosophy, Kumamoto University (2013)
  • Doctor of Medicine, Kurume University (2002)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Several neuronal diseases such as ischemic and hemorrhagic stroke and vascular dementia are associated with cerebral vascular injuries or pathologies. Cerebral vascular injuries cause blood brain barrier (BBB) disruption/dysfunction and BBB dysfunction is significantly associated with neurological diseases. Therefore, an understanding of the molecular mechanisms regulating BBB permeability and disruption is required for establishing efficacious therapeutic strategies.

There is currently a paucity of data available regarding the molecular mechanism of BBB dysfunction. microRNAs are small non-coding RNAs that regulate gene expression by targeting mRNAs. microRNAs have been implicated in the development and progression of various diseases, such as vascular disease. However the role of microRNAs on BBB breakdown or permeability remains unclear. We aim to determine the role of candidate microRNAs in BBB breakdown and consequently establish novel prevention and therapeutic interventions.

Publications

All Publications


  • Diabetic Cardiovascular Disease Induced by Oxidative Stress INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Kayama, Y., Raaz, U., Jagger, A., Adam, M., Schellinger, I. N., Sakamoto, M., Suzuki, H., Toyama, K., Spin, J. M., Tsao, P. S. 2015; 16 (10): 25234-25263
  • Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus CIRCULATION RESEARCH Raaz, U., Schellinger, I. N., Chernogubova, E., Warnecke, C., Kayama, Y., Penov, K., Hennigs, J. K., Salomons, F., Eken, S., Emrich, F. C., Zheng, W. H., Adam, M., Jagger, A., Nakagami, F., Toh, R., Toyama, K., Deng, A., Buerke, M., Maegdefessel, L., Hasenfuss, G., Spin, J. M., Tsao, P. S. 2015; 117 (6): 513-524
  • ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice SCIENTIFIC REPORTS Toyama, K., Koibuchi, N., Hasegawa, Y., Uekawa, K., Yasuda, O., Sueta, D., Nakagawa, T., Ma, M., Kusaka, H., Lin, B., Ogawa, H., Ichijo, H., Kim-Mitsuyama, S. 2015; 5

    Abstract

    Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density, and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment.

    View details for DOI 10.1038/srep10844

    View details for Web of Science ID 000355860800001

    View details for PubMedID 26044555

  • DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice CARDIOVASCULAR DIABETOLOGY Ma, M., Hasegawa, Y., Koibuchi, N., Toyama, K., Uekawa, K., Nakagawa, T., Lin, B., Kim-Mitsuyama, S. 2015; 14

    Abstract

    It is unclear whether dipeptidylpeptidase-4 (DPP-4) inhibition can counteract the impairment of cognitive function and brain injury caused by transient cerebral ischemia in type 2 diabetes. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration following transient cerebral ischemia can ameliorate cognitive impairment and brain injury in diabetic mice.db/db mice, a model of obese type 2 diabetes, were subjected to transient cerebral ischemia by 17 min of bilateral common carotid artery occlusion (BCCAO), and were administered (1) vehicle or (2) linagliptin for 8 weeks or 1 week. For the long-term experiment on 8 weeks of linagliptin treatment, cognitive function, and volume and neuronal cell number of hippocampus and cortex were estimated in each group of mice. For the short-term experiment on 1 week of linagliptin treatment, cerebral IgG extravasation, Iba-1 positive cell number (reactive microglia), oxidative stress, and claudin-5 and gp91phox protein levels were measured in each group of mice.Linagliptin administration almost completely suppressed the circulating DPP-4 activity in db/db mice, but did not significantly reduce blood glucose or ameliorate glucose intolerance in db/db mice. Linagliptin administration following transient cerebral ischemia significantly counteracted cognitive impairment in diabetic mice, as estimated by water maze test and passive avoidance test. Linagliptin administration ameliorated the decrease in cerebral volume and neuronal cell number in hippocampus and cortex of diabetic mice. Linagliptin administration significantly reduced the increase in cerebral IgG extravasation and the increase in reactive microglia caused by transient cerebral ischemia in diabetic mice. Furthermore, linagliptin significantly suppressed the increase in cerebral oxidative stress in transient cerebral ischemia-subjected diabetic mice. Furthermore, linagliptin significantly increased cerebral claudin-5 and significantly decreased gp91phox in diabetic mice subjected to transient cerebral ischemia.DPP-4 inhibition with linagliptin counteracted cognitive impairment and brain atrophy induced by transient cerebral ischemia in diabetic mice, independently of blood glucose lowering effect. This cerebroprotective effect of linagliptin was associated with the suppression of blood-brain barrier disruption and the attenuation of cerebral oxidative stress. Thus, our present work highlights DPP-4 inhibition as a promising therapeutic strategy for cognitive impairment and cerebral vascular complications in type 2 diabetes.

    View details for DOI 10.1186/s12933-015-0218-z

    View details for Web of Science ID 000355969900001

    View details for PubMedID 25986579

  • Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway ATHEROSCLEROSIS Kurokawa, H., Sugiyama, S., Nozaki, T., Sugamura, K., Toyama, K., Matsubara, J., Fujisue, K., Ohba, K., Maeda, H., Konishi, M., Akiyama, E., Sumida, H., Izumiya, Y., Yasuda, O., Kim-Mitsuyama, S., Ogawa, H. 2015; 239 (2): 375-385

    Abstract

    Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. Telmisartan is a unique angiotensin II type I receptor blocker that has been shown to prevent cardiovascular events in high risk patients. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. This study assessed whether telmisartan enhances mitochondrial function and alters cellular functions via AMPK in human coronary artery endothelial cells (HCAECs).In cultured HCAECs, telmisartan significantly enhanced mitochondrial activity assessed by mitochondrial reductase activity and intracellular ATP production and increased the expression of mitochondria related genes. Telmisartan prevented cellular senescence and exhibited the anti-apoptotic and pro-angiogenic properties. The expression of genes related anti-oxidant and pro-angiogenic properties were increased by telmisartan. Telmisartan increased endothelial NO synthase and AMPK phosphorylation. Peroxisome proliferator-activated receptor gamma signaling was not involved in telmisartan-induced improvement of mitochondrial function. All of these effects were abolished by inhibition of AMPK.Telmisartan enhanced mitochondrial activity and exhibited anti-senescence effects and improving endothelial function through AMPK in HCAECs. Telmisartan could provide beneficial effects on vascular diseases via enhancement of mitochondrial activity and modulating endothelial function through AMPK activation.

    View details for DOI 10.1016/j.atherosclerosis.2015.01.037

    View details for Web of Science ID 000351061600014

    View details for PubMedID 25682036

  • Telmisartan Exerts Sustained Blood Pressure Control and Reduces Blood Pressure Variability in Metabolic Syndrome by Inhibiting Sympathetic Activity AMERICAN JOURNAL OF HYPERTENSION Sueta, D., Koibuchi, N., Hasegawa, Y., Toyama, K., Uekawa, K., Katayama, T., Ma, M., Nakagawa, T., Ogawa, H., Kim-Mitsuyama, S. 2014; 27 (12): 1464-1471

    Abstract

    Accumulating evidence on blood pressure (BP) reduction with various angiotensin II receptor blockers (ARBs) show that the magnitudes and durations of BP control differ across ARBs. However, the mechanism of ARBs is unknown. This work was undertaken to compare telmisartan and valsartan in duration of BP control, BP variability, and effects on the autonomic nervous system.Using radiotelemetry combined with spectral analysis with a fast Fourier transformation algorithm, we compared the effects of various doses of telmisartan and valsartan on BP and its variability during dark (active phase) and light (inactive phase) periods over 5 weeks in SHR/NDmcr-cp(+/+)(SHRcp) rats, a model of metabolic syndrome. We also compared the effects of these ARBs on autonomic nervous system, central oxidative stress, and inflammation in SHRcp rats.Telmisartan exerted a longer-lasting BP-lowering effect and greater attenuation of BP variability in SHRcp than valsartan. Telmisartan decreased low frequency power of systolic BP and increased spontaneous baroreflex gain in SHRcp during both the dark and light periods more than valsartan. Telmisartan reduced 24-hour urinary norepinephrine excretion more than valsartan. Furthermore, telmisartan attenuated oxidative stress and the numbers of gp91(phox)-positive cells and activated microglia and astrocytes in the rostral ventrolateral medulla of SHRcp rats more than valsartan.The superiority of telmisartan over valsartan in sustained BP control and reduction of BP variability was attributed to more suppression of sympathetic activity and more improvement of baroreceptor reflex. The greater suppression of sympathetic activity by telmisartan appeared to be partially mediated by a stronger amelioration of central oxidative stress.

    View details for DOI 10.1093/ajh/hpu076

    View details for Web of Science ID 000345782100005

    View details for PubMedID 24871627

  • DPP-4 inhibitor linagliptin ameliorates cardiovascular injury in salt-sensitive hypertensive rats independently of blood glucose and blood pressure CARDIOVASCULAR DIABETOLOGY Koibuchi, N., Hasegawa, Y., Katayama, T., Toyama, K., Uekawa, K., Sueta, D., Kusaka, H., Ma, M., Nakagawa, T., Lin, B., Kim-Mitsuyama, S. 2014; 13

    Abstract

    It remains to be elucidated whether dipeptidylpeptidase-4 (DPP-4) inhibitor can ameliorate cardiovascular injury in salt-sensitive hypertension. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration initiated after onset of hypertension and cardiac hypertrophy can ameliorate cardiovascular injury in Dahl salt-sensitive hypertensive rats (DS rats).High-salt loaded DS rats with established hypertension and cardiac hypertrophy were divided into two groups, and were orally given (1) vehicle or (2) linagliptin (3mg/kg/day) once a day for 4weeks, and cardiovascular protective effects of linagliptin in DS rats were evaluated.Linagliptin did not significantly affect blood pressure and blood glucose levels in DS rats. Linagliptin significantly lessened cardiac hypertrophy in DS rats, as estimated by cardiac weight and echocardiographic parameters. Linagliptin significantly ameliorated cardiac fibrosis, cardiac macrophage infiltration, and coronary arterial remodeling in DS rats. Furthermore, linagliptin significantly mitigated the impairment of vascular function in DS rats, as shown by the improvement of acetylcholine-induced or sodium nitroprusside-induced vascular relaxation by linagliptin. These cardiovascular protective effects of linagliptin were associated with the attenuation of oxidative stress, NADPH oxidase subunits, p67phox and p22 phox, and angiotensin-converting enzyme (ACE).Our results provided the experimental evidence that linagliptin treatment initiated after the appearance of hypertension and cardiac hypertrophy protected against cardiovascular injury induced by salt-sensitive hypertension, independently of blood pressure and blood glucose. These beneficial effects of linagliptin seem to be attributed to the reduction of oxidative stress and ACE.

    View details for DOI 10.1186/s12933-014-0157-0

    View details for Web of Science ID 000346065400001

    View details for PubMedID 25471116

  • Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice CARDIOVASCULAR DIABETOLOGY Lin, B., Koibuchi, N., Hasegawa, Y., Sueta, D., Toyama, K., Uekawa, K., Ma, M., Nakagawa, T., Kusaka, H., Kim-Mitsuyama, S. 2014; 13

    Abstract

    There has been uncertainty regarding the benefit of glycemic control with antidiabetic agents in prevention of diabetic macrovascular disease. Further development of novel antidiabetic agents is essential for overcoming the burden of diabetic macrovascular disease. The renal sodium glucose co-transporter 2 (SGLT2) inhibitor is a novel antihyperglycemic agent for treatment of type 2 diabetes. This work was performed to determine whether empagliflozin, a novel SGLT2 inhibitor, can ameliorate cardiovascular injury and cognitive decline in db/db mouse, a model of obesity and type 2 diabetes.(1) Short-term experiment: The first experiment was performed to examine the effect of 7 days of empagliflozin treatment on urinary glucose excretion and urinary electrolyte excretion in db/db mice. (2) Long-term experiment: The second experiment was undertaken to examine the effect of 10 weeks of empagliflozin treatment on cardiovascular injury, vascular dysfunction, cognitive decline, and renal injury in db/db mice.(1) Short-term experiment: Empagliflozin administration significantly increased urinary glucose excretion, urine volume, and urinary sodium excretion in db/db mice on day 1, but did not increase these parameters from day 2. However, blood glucose levels in db/db mice were continuously decreased by empagliflozin throughout 7 days of the treatment. (2) Long-term experiment: Empagliflozin treatment caused sustained decrease in blood glucose in db/db mice throughout 10 weeks of the treatment and significantly slowed the progression of type 2 diabetes. Empagliflozin significantly ameliorated cardiac interstitial fibrosis, pericoronary arterial fibrosis, coronary arterial thickening, cardiac macrophage infiltration, and the impairment of vascular dilating function in db/db mice, and these beneficial effects of empagliflozin were associated with attenuation of oxidative stress in cardiovascular tissue of db/db mice. Furthermore, empagliflozin significantly prevented the impairment of cognitive function in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor. Empagliflozin ameliorated albuminuria, and glomerular injury in db/db mice.Glycemic control with empagliflozin significantly ameliorated cardiovascular injury and remodeling, vascular dysfunction, and cognitive decline in obese and type 2 diabetic mice. Thus, empagliflozin seems to be potentially a promising therapeutic agent for diabetic macrovascular disease and cognitive decline.

    View details for DOI 10.1186/s12933-014-0148-1

    View details for Web of Science ID 000346063100001

    View details for PubMedID 25344694

  • Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade ATHEROSCLEROSIS Sueta, D., Koibuchi, N., Hasegawa, Y., Toyama, K., Uekawa, K., Katayama, T., Ma, M., Nakagawa, T., Waki, H., Maeda, M., Ogawa, H., Kim-Mitsuyama, S. 2014; 236 (1): 101-107

    Abstract

    Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR).We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence.Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan.ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.

    View details for DOI 10.1016/j.atherosclerosis.2014.06.016

    View details for Web of Science ID 000342412000013

    View details for PubMedID 25016364

  • Statins combined with exercise are associated with the increased renal function mediated by high-molecular-weight adiponectin in coronary artery disease patients JOURNAL OF CARDIOLOGY Toyama, K., Sugiyama, S., Oka, H., Iwasaki, Y., Sumida, H., Tanaka, T., Tayama, S., Jinnouchi, H., Ogawa, H. 2014; 64 (2): 91-97

    Abstract

    Statins and exercise therapy are clinically effective in preventing cardiovascular events in patients with coronary artery disease (CAD). The aim of this study was to determine the effects of statins combined with exercise on the renal function of CAD patients.We performed a sub-analysis of a clinical trial that determined the 20-week-effects of two statins (rosuvastatin, n=14; atorvastatin, n=14) combined with regular exercise on renal function, as assessed by the estimated glomerular filtration rates (eGFRs) of CAD patients.The combination of statins and exercise therapy increased eGFRs from 61.116.6 at baseline to 65.816.8ml/min/per 1.73m(2) (p=0.03), increased serum levels of high-molecular-weight (HMW) adiponectin, increased ubiquinol/low-density lipoprotein cholesterol (LDL-C) ratios, and decreased high sensitivity C-reactive protein (hs-CRP). Changes in HMW-adiponectin, ubiquinol/LDL-C ratios and hs-CRP were significantly correlated with changes in eGFR (r=0.597, p=0.001; r=0.437, p=0.02; and r=-0.473, p=0.01, respectively). Treatment-induced increases in HMW-adiponectin independently correlated with the increases in eGFR (?=0.513, p=0.02) in a multivariate analysis. Both atorvastatin and rosuvastatin combined with regular exercise produced increases in eGFR. The patients treated with rosuvastatin exhibited significant improvements in eGFR.Statins combined with exercise significantly increased eGFR in CAD patients, and these improvements in renal function were correlated with increases in HMW-adiponectin levels. The statins-exercise combination treatment may have provided clinical benefits for patients with CAD partly through the improvement in renal function.

    View details for DOI 10.1016/j.jjcc.2013.11.018

    View details for Web of Science ID 000349278100003

    View details for PubMedID 24457019

  • Rosuvastatin Ameliorates Early Brain Injury after Subarachnoid Hemorrhage via Suppression of Superoxide Formation and Nuclear Factor-Kappa B Activation in Rats JOURNAL OF STROKE & CEREBROVASCULAR DISEASES Uekawa, K., Hasegawa, Y., Ma, M., Nakagawa, T., Katayama, T., Sueta, D., Toyama, K., Kataoka, K., Koibuchi, N., Kawano, T., Kuratsu, J., Kim-Mitsuyama, S. 2014; 23 (6): 1429-1439

    Abstract

    Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been suggested to possess pleiotropic effects, including antioxidant and anti-inflammatory properties. We investigated the protective effects of pretreatment with rosuvastatin, a relatively hydrophilic statin, on early brain injury (EBI) after a subarachnoid hemorrhage (SAH), using the endovascular perforation SAH model.Eighty-six male Sprague-Dawley rats were randomly divided into 3 groups: (1) sham operation, (2) SAH+vehicle, and (3) SAH+10 mg/kg rosuvastatin. Rosuvastatin or vehicle was orally administered to rats once daily from 7 days before to 1 day after the SAH operation. After SAH, we examined the effects of rosuvastatin on the neurologic score, brain water content, neuronal cell death estimated by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate nick end labeling staining, blood-brain barrier disruption by immunoglobulin G (IgG) extravasation, oxidative stress, and proinflammatory molecules.Compared with the vehicle group, rosuvastatin significantly improved the neurologic score and reduced the brain water content, neuronal cell death, and IgG extravasation. Rosuvastatin inhibited brain superoxide production, nuclear factor-kappa B (NF-?B) activation, and the increase in activated microglial cells after SAH. The increased expressions of tumor necrosis factor-alpha, endothelial matrix metalloproteinase-9, and neuronal cyclooxygenase-2 induced by SAH were prevented by rosuvastatin pretreatment.The present study demonstrates that rosuvastatin pretreatment ameliorates EBI after SAH through the attenuation of oxidative stress and NF-?B-mediated inflammation.

    View details for DOI 10.1016/j.jstrokecerebrovasdis.2013.12.004

    View details for Web of Science ID 000338475600026

    View details for PubMedID 24529602

  • Apoptosis Signal- Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Toyama, K., Koibuchi, N., Uekawa, K., Hasegawa, Y., Kataoka, K., Katayama, T., Sueta, D., Ma, M. J., Nakagawa, T., Yasuda, O., Tomimoto, H., Ichijo, H., Ogawa, H., Kim-Mitsuyama, S. 2014; 34 (3): 616-625

    Abstract

    There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions.A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1(-/-)) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-? expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1(-/-) mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1(-/-) mice. Cerebral nitrotyrosine was increased in wild-type and ASK1(-/-) BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-? stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1(-/-) mice.Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood-brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment.

    View details for DOI 10.1161/ATVBAHA.113.302440

    View details for Web of Science ID 000332996600019

    View details for PubMedID 24371084

  • Renal Denervation Prevents Stroke and Brain Injury via Attenuation of Oxidative Stress in Hypertensive Rats JOURNAL OF THE AMERICAN HEART ASSOCIATION Nakagawa, T., Hasegawa, Y., Uekawa, K., Ma, M., Katayama, T., Sueta, D., Toyama, K., Kataoka, K., Koibuchi, N., Maeda, M., Kuratsu, J., Kim-Mitsuyama, S. 2013; 2 (5)

    Abstract

    Although renal denervation (RD) is shown to reduce blood pressure significantly in patients with resistant hypertension, the benefit of RD in prevention of stroke is unknown. We hypothesized that RD can prevent the incidence of stroke and brain injury in hypertensive rats beyond blood pressure lowering.High-salt-loaded, stroke-prone, spontaneously hypertensive rats (SHRSP) were divided into 4 groups: (1) control; (2) sham operation; (3) bilateral RD; and (4) hydralazine administration to examine the effect of RD on stroke and brain injury of SHRSP. RD significantly reduced the onset of neurological deficit and death in SHRSP, and this protection against stroke by RD was associated with the increase in cerebral blood flow (CBF), the suppression of blood-brain barrier disruption, the limitation of white matter (WM) lesions, and the attenuation of macrophage infiltration and activated microglia. Furthermore, RD significantly attenuated brain oxidative stress, and NADPH oxidase subunits, P67 and Rac1 in SHRSP. On the other hand, hydralazine, with similar blood pressure lowering to RD, did not significantly suppress the onset of stroke and brain injury in SHRSP. Furthermore, RD prevented cardiac remodeling and vascular endothelial impairment in SHRSP.Our present work provided the first experimental evidence that RD can prevent hypertensive stroke and brain injury, beyond blood pressure lowering, thereby highlighting RD as a promising therapeutic strategy for stroke as well as hypertension.

    View details for DOI 10.1161/JAHA.113.000375

    View details for Web of Science ID 000326343200030

    View details for PubMedID 24125845

  • Response: Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2 '-deoxyguanosine and biopyrrin in atrial fibrillation: Effect of sinus rhythm restoration INTERNATIONAL JOURNAL OF CARDIOLOGY Toyama, K., Yamabe, H., Uemura, T., Ogawa, H. 2013; 168 (2): 1616-1616

    View details for DOI 10.1016/j.ijcard.2013.01.020

    View details for Web of Science ID 000325412800207

    View details for PubMedID 23414738

  • Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2 '-deoxyguanosine and biopyrrin in atrial fibrillation: Effect of sinus rhythm restoration INTERNATIONAL JOURNAL OF CARDIOLOGY Toyama, K., Yamabe, H., Uemura, T., Nagayoshi, Y., Morihisa, K., Koyama, J., Kanazawa, H., Hoshiyama, T., Ogawa, H. 2013; 168 (1): 80-85

    Abstract

    Oxidative stress is considered to contribute to the pathological consequences of atrial fibrillation (AF). We examined the level of oxidative stress in AF patients and changes in its level following sinus rhythm restoration.Oxidative stress level was evaluated by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, and urinary biopyrrin, an oxidative metabolite of bilirubin. In Study 1, we compared 8-OHdG/creatinine levels between patients with permanent AF (AF-group, n=40) and sinus rhythm (SR-group, n=133). In Study 2, we examined the changes in 8-OHdG and biopyrrin levels in 36 patients with persistent AF following sinus rhythm restoration by electrical or pharmacological cardioversion (n=15) and radiofrequency catheter ablation (n=21).In Study 1, 8-OHdG/creatinine levels were significantly higher in AF-group than in SR-group (19.1 8.6 vs. 12.3 5.5 ng/mg, p<0.001). Multivariate analysis showed that the presence of AF was an independent factor that significantly correlated with 8-OHdG/creatinine level after adjustment for other covariates to oxidative stress (?=0.36, p<0.001). Sinus rhythm was maintained at the chronic phase in patients of all Study 2 (7.2 5.8 months after cardioversion or catheter ablation). 8-OHdG/creatinine and biopyrrin/creatinine levels at the chronic phase were significantly lower than those before cardioversion or catheter ablation (8.7 3.2 vs. 21.7 15.1 ng/mg, p<0.0001 and 1.7 1.1 vs. 3.0 1.9 mU/mg, p<0.0001).Oxidative stress level is significantly increased in AF patients, but can be improved by restoration of sinus rhythm. The results suggest that the pathogenic process of AF is promoted by AF itself through the production of oxidative stress.

    View details for DOI 10.1016/j.ijcard.2012.09.068

    View details for Web of Science ID 000325409800026

    View details for PubMedID 23040081

  • Long-Term Renal Denervation Normalizes Disrupted Blood Pressure Circadian Rhythm and Ameliorates Cardiovascular Injury in a Rat Model of Metabolic Syndrome JOURNAL OF THE AMERICAN HEART ASSOCIATION Katayama, T., Sueta, D., Kataoka, K., Hasegawa, Y., Koibuchi, N., Toyama, K., Uekawa, K., Ma Mingjie, M. J., Nakagawa, T., Maeda, M., Ogawa, H., Kim-Mitsuyama, S. 2013; 2 (4)

    Abstract

    Although renal denervation significantly reduces blood pressure in patients with resistant hypertension, the role of the renal nerve in hypertension with metabolic syndrome is unknown. We investigated the impact of long-term renal denervation on SHR/NDmcr-cp(+/+) (SHRcp) rats, a useful rat model of metabolic syndrome, to determine the role of the renal nerve in hypertension with metabolic syndrome.SHRcp rats were divided into (1) a renal denervation (RD) group and (2) a sham operation group (control) to examine the effects of long-term RD on blood pressure circadian rhythm, renal sodium retention-related molecules, the renin-angiotensin-aldosterone system, metabolic disorders, and organ injury. RD in SHRcp rats not only significantly reduced blood pressure but also normalized blood pressure circadian rhythm from the nondipper to the dipper type, and this improvement was associated with an increase in urinary sodium excretion and the suppression of renal Na(+)-Cl(-) cotransporter upregulation. RD significantly reduced plasma renin activity. RD significantly prevented cardiovascular remodeling and impairment of vascular endothelial function and attenuated cardiovascular oxidative stress. However, RD failed to ameliorate obesity, metabolic disorders, and renal injury and failed to reduce systemic sympathetic activity in SHRcp rats.By including the upregulation of the Na(+)-Cl(-) cotransporter, the renal sympathetic nerve is involved in the disruption of blood pressure circadian rhythm as well as hypertension in metabolic syndrome. Thus, RD seems to be a useful therapeutic strategy for hypertension with metabolic syndrome.

    View details for DOI 10.1161/JAHA.113.000197

    View details for Web of Science ID 000326340900017

    View details for PubMedID 23974905

  • Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation BRAIN RESEARCH Ma, M., Uekawa, K., Hasegawa, Y., Nakagawa, T., Katayama, T., Sueta, D., Toyama, K., Kataoka, K., Koibuchi, N., Kuratsu, J., Kim-Mitsuyama, S. 2013; 1519: 87-94

    Abstract

    This study aimed to examine the potential protective effect of rosuvastatin against cerebral ischemia/reperfusion injury and its mechanisms. Forty-eight male SD rats underwent 90 min of transient middle cerebral artery occlusion (tMCAO), followed by reperfusion. Rats were orally given (1) rosuvastatin 1mg/kg, (2) rosuvastatin 10mg/kg or (3) water (vehicle) once a day from 7 days before to 1 day after induction of tMCAO. Neurological score, infarct volume, and oxidative stress-related molecules (assessed by immunohistochemistry, dihydroethidium staining, or western blotting) were estimated at 24h after reperfusion. Rosuvastatin prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The increases in activated microglia, macrophage, and superoxide levels usually caused by ischemia/reperfusion were significantly ameliorated by rosuvastatin. Rosuvastatin also inhibited the upregulation of gp91(phox) and p22phox, phosphorylation of nuclear factor-kappa B, and induction of cyclooxygenase 2 and inducible nitric oxide synthase, compared with vehicle. The results suggest that pretreatment with rosuvastatin may be a promising therapeutic strategy for cerebral ischemia/reperfusion injury, through attenuation of oxidative stress and inflammation.

    View details for DOI 10.1016/j.brainres.2013.04.040

    View details for Web of Science ID 000321473500010

    View details for PubMedID 23632378

  • Novel Mechanism for Disrupted Circadian Blood Pressure Rhythm in a Rat Model of Metabolic Syndrome-The Critical Role of Angiotensin II JOURNAL OF THE AMERICAN HEART ASSOCIATION Sueta, D., Kataoka, K., Koibuchi, N., Toyama, K., Uekawa, K., Katayama, T., Ma Mingjie, M. J., Nakagawa, T., Waki, H., Maeda, M., Yasuda, O., Matsui, K., Ogawa, H., Kim-Mitsuyama, S. 2013; 2 (3)
  • Combination Treatment of Rosuvastatin or Atorvastatin, with Regular Exercise Improves Arterial Wall Stiffness in Patients with Coronary Artery Disease PLOS ONE Toyama, K., Sugiyama, S., Oka, H., Iwasaki, Y., Sumida, H., Tanaka, T., Tayama, S., Jinnouchi, H., Ogawa, H. 2012; 7 (7)

    Abstract

    Statin- and exercise-therapy are both clinically beneficial by preventing cardiovascular events in patients with coronary artery disease (CAD). However, there is no information on the vascular effects of the combination of statins and exercise on arterial wall stiffness in CAD patients.The present study is a sub-analysis of PRESET study that determined the effects of 20-week treatment with statins (rosuvastatin, n=14, atorvastatin, n=14) combined with regular exercise on arterial wall stiffness assessed by measurement of brachial and ankle pulse wave velocity (baPWV) in CAD patients.The combination of statins and regular exercise significantly improved exercise capacity, lipid profile, including low- and high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hs-CRP), baPWV (baseline: 1747 355, at 20 weeks of treatment: 1627 271 cm/s, p=0.008), and basophil count (baseline: 42 32, 20 weeks: 26 15 cells/L, p=0.007), but had no effect on blood pressure (baseline: 125 22, 20 weeks: 121 16 mmHg). Changes in baPWV correlated significantly with changes in basophil count (r=0.488, p=0.008), but not with age, lipids profile, exercise capacity, or hs-CRP.In CAD patients, the combination treatment with statins and exercise resulted in significant amelioration of arterial wall stiffness, at least in part, through reduction of circulating basophils.

    View details for DOI 10.1371/journal.pone.0041369

    View details for Web of Science ID 000306956300083

    View details for PubMedID 22829944

  • Amlodipine Enhances Amelioration of Vascular Insulin Resistance, Oxidative Stress, and Metabolic Disorders by Candesartan in Metabolic Syndrome Rats AMERICAN JOURNAL OF HYPERTENSION Sueta, D., Nakamura, T., Dong, Y., Kataoka, K., Koibuchi, N., Yamamoto, E., Toyama, K., Yasuda, O., Ogawa, H., Kim-Mitsuyama, S. 2012; 25 (6): 704-710

    Abstract

    The pharmacological advantage of combination of an angiotensin receptor blocker (ARB) and a calcium-channel blocker (CCB) is not fully defined. This study was undertaken to elucidate the potential benefit of their combination in metabolic syndrome.SHR/NDmcr-cp (SHRcp), a rat model of human metabolic syndrome, were divided into four groups, and were administered (i) vehicle, (ii) candesartan (an ARB) 0.3 mg/kg/day, (iii) amlodipine (a CCB) 3 mg/kg/day, and (iv) candesartan 0.3 mg/kg/day plus amlodipine 3 mg/kg/day, for 4 weeks.Candesartan, amlodipine, or their combination significantly ameliorated the impairment of vascular endothelium-dependent relaxation with acetylcholine in SHRcp. However, the impairment of insulin-induced vasodilation in SHRcp was partially improved by candesartan alone, but not by amlodipine alone. Interestingly, amlodipine added to candesartan synergistically enhanced the improvement of impaired insulin-induced vasodilation by candesartan, indicating the synergistic improvement of vascular insulin resistance by the combination of these drugs. Candesartan alone, but not amlodipine alone, significantly attenuated vascular superoxide and NADPH oxidase subunit p22phox in SHRcp. Amlodipine added to candesartan synergistically enhanced the reduction of vascular p22phox levels and superoxide by candesartan in SHRcp, suggesting the association of vascular insulin resistance with oxidative stress. Furthermore, the combination of candesartan with amlodipine synergistically decreased the increase in visceral adipocyte size, serum free-fatty acid, and tumor necrosis factor-? in SHRcp.ARB and CCB combination synergistically ameliorated vascular insulin resistance in metabolic syndrome, being associated with the synergistic attenuation of vascular oxidative stress and metabolic disorders.

    View details for DOI 10.1038/ajh.2012.26

    View details for Web of Science ID 000304188600014

    View details for PubMedID 22421905

  • Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF HYPERTENSION RESEARCH Nako, H., Kataoka, K., Koibuchi, N., Dong, Y., Toyama, K., Yamamoto, E., Yasuda, O., Ichijo, H., Ogawa, H., Kim-Mitsuyama, S. 2012; 35 (2): 194-200

    Abstract

    This study was undertaken to elucidate a novel mechanism underlying angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or heart failure, were orally given irbesartan (an AT1 receptor blocker), tempol (a superoxide dismutase mimetic) or hydralazine (a vasodilator). Irbesartan significantly ameliorated left ventricular ischemia and prevented the development of cardiac hypertrophy and fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant cardiac hypertrophy and fibrosis displayed decreased myocardial vascular endothelial growth factor (VEGF) expression and increased cardiac apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with irbesartan significantly reversed these phenotypes. Tempol treatment of DS rats mimicked all the above-mentioned effects of irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in angiotensin II-induced progression of cardiac injury.

    View details for DOI 10.1038/hr.2011.175

    View details for Web of Science ID 000300316000011

    View details for PubMedID 22089532

  • Beneficial Effects of Combination of Valsartan and Amlodipine on Salt-Induced Brain Injury in Hypertensive Rats JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Dong, Y., Kataoka, K., Tokutomi, Y., Nako, H., Nakamura, T., Toyama, K., Sueta, D., Koibuchi, N., Yamamoto, E., Ogawa, H., Kim-Mitsuyama, S. 2011; 339 (2): 358-366

    Abstract

    The optimum antihypertensive treatment for prevention of hypertensive stroke has yet to be elucidated. This study was undertaken to examine the benefit of a combination of valsartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, in prevention of high-salt-induced brain injury in hypertensive rats. High-salt-loaded stroke-prone spontaneously hypertensive rats (SHRSPs) were given 1) vehicle, 2) valsartan (2 mg/kg/day), 3) amlodipine (2 mg/kg/day), or 4) a combination of valsartan and amlodipine for 4 weeks. The effects on brain injury were compared between all groups. High-salt loading in SHRSPs caused the reduction of cerebral blood flow (CBF), cerebral hypoxia, white matter lesions, glial activation, AT1 receptor up-regulation, endothelial nitric-oxide synthase (eNOS) uncoupling, inducible nitric-oxide synthase induction, and nitroxidative stress. Valsartan, independently of blood pressure, enhanced the protective effects of amlodipine against brain injury, white matter lesions, and glial activation in salt-loaded SHRSPs. These beneficial effects of valsartan added to amlodipine were associated with an additive improvement in CBF and brain hypoxia because of an additive improvement in cerebral arteriolar remodeling and vascular endothelial dysfunction. Furthermore, valsartan added to amlodipine enhanced the attenuation of cerebral nitroxidative stress through an additive suppression of eNOS uncoupling. Valsartan, independently of blood pressure, augmented the protective effects of amlodipine against brain injury in salt-loaded hypertensive rats through an improvement in brain circulation attributed to nitroxidative stress. Our results suggest that the combination of valsartan and amlodipine may be a promising strategy for the prevention of salt-related brain injury in hypertensive patients.

    View details for DOI 10.1124/jpet.111.182576

    View details for Web of Science ID 000296464800005

    View details for PubMedID 21807884

  • Attenuation of Brain Damage and Cognitive Impairment by Direct Renin Inhibition in Mice With Chronic Cerebral Hypoperfusion HYPERTENSION Dong, Y., Kataoka, K., Toyama, K., Sueta, D., Koibuchi, N., Yamamoto, E., Yata, K., Tomimoto, H., Ogawa, H., Kim-Mitsuyama, S. 2011; 58 (4): 635-U247

    Abstract

    The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67(phox)-related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia.

    View details for DOI 10.1161/HYPERTENSIONAHA.111.173534

    View details for Web of Science ID 000294859200033

    View details for PubMedID 21859961

  • Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease FASEB JOURNAL Dong, Y., Kataoka, K., Tokutomi, Y., Nako, H., Nakamura, T., Toyama, K., Sueta, D., Koibuchi, N., Yamamoto, E., Ogawa, H., Kim-Mitsuyama, S. 2011; 25 (9): 2911-2920

    Abstract

    The purpose of this work was to test whether brain-penetrating angiotensin-converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain-penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-? (A?)????. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing A? in the brain. Perindopril, without affecting brain A? deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.

    View details for DOI 10.1096/fj.11-182873

    View details for Web of Science ID 000294435200007

    View details for PubMedID 21593435

  • Novel mechanism of salt-induced glomerular injury: critical role of eNOS and angiotensin II JOURNAL OF HYPERTENSION Nakamura, T., Kataoka, K., Tokutomi, Y., Nako, H., Toyama, K., Dong, Y., Koibuchi, N., Yamamoto, E., Yasuda, O., Ogawa, H., Kim-Mitsuyama, S. 2011; 29 (8): 1528-1535

    Abstract

    The present study was undertaken to examine the role of endothelial nitric oxide synthase (eNOS) in salt-sensitive renal injury.The effects of high-salt diet on renal injury were compared between wild-type and eNOS-/- mice. To examine the role of glomerular angiotensin II and oxidative stress, high-salt fed eNOS-/- mice were given irbesartan, an angiotensin receptor blocker, or tempol, an antioxidant.Four weeks of high-salt diet in wild-type mice, which rapidly caused glomerular eNOS activation and subsequent increase in nitric oxide, did not at all induce renal injury, indicating that wild-type mice are salt-resistant. On the contrary, high-salt diet in eNOS-/- mice, which little increased nitric oxide, rapidly increased urinary albumin excretion, followed by glomerular macrophage infiltration and glomerular sclerosis. Thus, eNOS deficiency caused salt-sensitive glomerular injury. Salt-induced glomerular injury in eNOS-/- mice was preceded by rapid enhancement of glomerular superoxide followed by enhancement of glomerular endothelial angiotensinogen and angiotensin II. Irbesartan and tempol, independently of blood pressure, markedly prevented salt-induced glomerular injury in eNOS-/- mice, and these protective effects were attributed to the attenuation of glomerular oxidative stress and glomerular angiotensinogen-derived angiotensin II.We propose that eNOS dysfunction plays a causative role in salt-induced glomerular injury, through augmentation of glomerular oxidative stress-induced angiotensinogen.

    View details for DOI 10.1097/HJH.0b013e328348ca95

    View details for Web of Science ID 000292688400010

    View details for PubMedID 21720272

  • Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-gamma-dependent activity BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Toyama, K., Nakamura, T., Kataoka, K., Yasuda, O., Fukuda, M., Tokutomi, Y., Dong, Y., Ogawa, H., Kim-Mitsuyama, S. 2011; 410 (3): 508-513

    Abstract

    Experimental and clinical data support the notion that peroxisome proliferator-activated receptor ? (PPAR?) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR? agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR? activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR? antagonist), and losartan with no PPAR? activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF?B) activation and tumor necrosis factor ?. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR? activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPAR? in db/db mice and this effect of telmisartan was cancelled by the coadministration of GW9662. Our data provided the first evidence indicating that PPAR? activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. PPAR? activity of telmisartan was involved in the normalization of vascular PPAR? downregulation in diabetic mice. Thus, telmisartan seems to exert vascular protective effects in hypertensive patients with diabetes.

    View details for DOI 10.1016/j.bbrc.2011.06.012

    View details for Web of Science ID 000292797700024

    View details for PubMedID 21679694

  • Improvement effect on endothelial function in patients with congestive heart failure treated with cardiac resynchronization therapy JOURNAL OF CARDIOLOGY Enomoto, K., Yamabe, H., Toyama, K., matsuzawa, Y., Yamamuro, M., Uemura, T., Morihisa, K., Iwashita, S., Kaikita, K., Sugiyama, S., Ogawa, H. 2011; 58 (1): 69-73

    Abstract

    Cardiac resynchronization therapy (CRT) is a beneficial strategy to improve severe cardiac dysfunction in patients with congestive heart failure (CHF). The improvement of endothelial function in CHF patients treated with CRT is reflected in the mortality risk reduction. However the precise mechanisms of the relationship between CRT and vascular endothelial function have not been well discussed.Twenty-two severe consecutive CHF patients associated with dilated cardiomyopathy [New York Heart Association (NYHA) class 3.3 0.5, left ventricular ejection fraction (LVEF) 24.4 5.9%] were included in this study. We evaluated endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), between optimal medical therapy alone group (medical therapy group: n = 10) and CRT group (n = 12) at the study enrolment and 12 weeks later. Furthermore we analyzed the association between the RH-PAT and cardiac function.Both therapies significantly and equally improved NYHA class, LVEF, end-diastolic left ventricular dimension and plasma levels of brain natriuretic peptide (BNP). CRT significantly increased RH-PAT index (medical therapy group: 1.5 0.2 to 1.5 0.3, p = 0.824; CRT group: 1.4 0.2 to 1.7 0.4, p = 0.003) and cardiac output (medical therapy group: 3.3 1.1 to 3.5 1.0, p = 0.600; CRT group: 2.7 0.6 to 4.3 1.5, p = 0.001), compared to the medical therapy group. There was significant positive correlation between the change in RH-PAT index and cardiac output (r = 0.600, p = 0.003).CRT significantly improved endothelial function through the improvement of cardiac output in CHF patients, compared to optimal medical therapy.

    View details for DOI 10.1016/j.jjcc.2011.01.010

    View details for Web of Science ID 000292902500010

    View details for PubMedID 21493043

  • Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease ATHEROSCLEROSIS Toyama, K., Sugiyama, S., Oka, H., Iwasaki, Y., Sumida, H., Tanaka, T., Tayama, S., Jinnouchi, H., Matsui, K., Ogawa, H. 2011; 217 (1): 158-164

    Abstract

    Coenzyme Q10 levels are low in patients with coronary artery disease (CAD), and increasing or preserving coenzyme Q10 could be a beneficial strategy. Exercise and statins improve high-density lipoprotein cholesterol (HDL-C) levels. However, statins inhibit coenzyme Q10 biosynthesis, and the combination of statins with coenzyme Q10 supplementation increases HDL-C compared to statins alone. We compared the effects of two statins (rosuvastatin and atorvastatin) combined with exercise on coenzyme Q10 and HDL-C levels in CAD patients.After randomizing 28 CAD patients to rosuvastatin (n=14) and atorvastatin (n=14) groups, patients performed weekly in-hospital aerobic exercise and daily home exercise for 20 weeks. We measured serum lipids, ubiquinol, and exercise capacity.Both statins equally improved exercise capacity and lowered low-density lipoprotein cholesterol and triglyceride levels. Rosuvastatin significantly increased HDL-C (rosuvastatin, +12 9 mg/dL [+30%], atorvastatin, +5 5 mg/dL [+13%], p=0.014) and apolipoprotein A1 (ApoA1) (rosuvastatin, +28.3 20.7 mg/dL, atorvastatin, +13.4 12.0 mg/dL, p=0.030) compared to atorvastatin. Atorvastatin significantly decreased serum ubiquinol (731 238 to 547 219 nmol/L, p=0.001), but rosuvastatin (680233 to 668 299 nmol/L, p=0.834) did not. There was a significant positive correlation between changes in ubiquinol and ApoA1 (r=0.518, p=0.005). Multivariate regression analysis showed that changes in ubiquinol correlated significantly with changes in ApoA1 after adjusting for age, sex, body mass index, and smoking (?=0.502, p=0.008).Compared to atorvastatin, rosuvastatin combined with exercise significantly preserved ubiquinol levels associated with an increase in HDL-C. Rosuvastatin with regular exercise could be beneficial for CAD patients.

    View details for DOI 10.1016/j.atherosclerosis.2011.02.050

    View details for Web of Science ID 000292731300025

    View details for PubMedID 21458815

  • Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice BRITISH JOURNAL OF PHARMACOLOGY Tokutomi, Y., Kataoka, K., Yamamoto, E., Nakamura, T., Fukuda, M., Nako, H., Toyama, K., Dong, Y., Ahmed, K. A., Sawa, T., Akaike, T., Kim-Mitsuyama, S. 2011; 162 (8): 1884-1893

    Abstract

    8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), formed nitric oxide (NO)-dependently, is a physiological second messenger, yet little is known about its role in the pathophysiology of vascular diseases. To study the pharmacological activity of 8-nitro-cGMP in diabetic mice, we compared its effects on vascular reactivity of aortas from non-diabetic and diabetic mice.Vascular tension recording was performed in thoracic aortic rings from wild-type (C57BL/6), non-diabetic db/+ and obese/diabetic db/db mice. Endothelial NO synthase (eNOS) uncoupling and superoxide were tested by Western blot and dihydroethidium fluorescence respectively.8-Nitro-cGMP, at concentrations up to 10 M, enhanced phenylephrine-induced contractions in aortas from C57BL/6 and db/+ mice, but not from db/db mice. This enhancement was not observed with 8-bromo-cGMP. Pretreatment of aortas from C57BL/6 and db/+ mice with l-NAME (100 M), superoxide dismutase (100 UmL(-1) ) or tiron (1 mM), abolished 8-nitro-cGMP-induced enhancement of the phenylephrine contraction. In 8-nitro-cGMP (10 M)-treated C57BL/6 aortas, eNOS dimer/monomer ratio was significantly decreased and vascular superoxide production increased, suggesting that 8-nitro-cGMP-induced superoxide production via eNOS uncoupling may mediate the enhancement of the phenylephrine contraction. At higher concentrations (>10 M), 8-nitro-cGMP produced relaxation of the phenylephrine-contracted aortas from C57BL/6, db/+ and db/db mice. The 8-nitro-cGMP-induced relaxation in db/db mouse aortas was found to be resistant to a phosphodiesterase 5 inhibitor, zaprinast (1 M).The vasodilator effect of 8-nitro-cGMP may contribute to amelioration of the vascular endothelial dysfunction in diabetic mice, representing a novel pharmacological approach to prevent the complications associated with diabetes.

    View details for DOI 10.1111/j.1476-5381.2011.01201.x

    View details for Web of Science ID 000288704500018

    View details for PubMedID 21232030

  • Exercise therapy correlates with improving renal function through modifying lipid metabolism in patients with cardiovascular disease and chronic kidney disease JOURNAL OF CARDIOLOGY Toyama, K., Sugiyama, S., Oka, H., Sumida, H., Ogawa, H. 2010; 56 (2): 142-146

    Abstract

    Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) are at high risk of cardiovascular mortality, thus therapies to improve renal function should be clinically investigated.We divided consecutive patients with CVD and CKD (n=19) into exercise (n=10) and non-exercise (n=9) therapy groups. Exercise therapy for 12 weeks significantly improved the anaerobic metabolic threshold (AT-V O?) and high-density lipoprotein cholesterol (HDL-C) levels, and reduced triglyceride levels. Exercise therapy also improved estimated glomerular filtration rate (eGFR). Change in eGFR correlated significantly and positively with change in AT-V O? and HDL-C, and negatively with change in triglyceride levels.Exercise therapy correlates with improving renal function in CVD patients with CKD through modifying lipid metabolism. Exercise therapy could be an effective clinical strategy to improve renal function.

    View details for DOI 10.1016/j.jjcc.2010.06.007

    View details for Web of Science ID 000281929300003

    View details for PubMedID 20696551

  • Primary Systemic Amyloidosis with Bloody Pericardial Effusion INTERNAL MEDICINE Toyama, K., Oka, H., Obata, K., Ogawa, H. 2009; 48 (10): 821-826

    Abstract

    A 73-year-old woman was admitted due to exertional dyspnea. It was considered that a large amount of pericardial effusion caused diastolic heart failure; pericardial paracentesis showed bloody effusion. There were no findings of malignancy or other abnormal findings in the examination. Further examinations were planned but she died of ventricular tachycardia attack. Pathological autopsy revealed primary systemic amyloidosis. Pathologically it was possible that the local inflammation (epicarditis) due to the deposition of amyloid in the epicardium and perivascular tissue caused the bloody effusion. There are no reports of primary systemic amyloidosis with hemorrhagic pericardial effusion. We report this rare case with pathological consideration.

    View details for DOI 10.2169/internalmedicine.48.1846

    View details for Web of Science ID 000266791900012

    View details for PubMedID 19443978

  • Platypnea-orthodeoxia syndrome combined with multiple congenital heart anomalies INTERNAL MEDICINE Nagayoshi, Y., Toyama, K., Kawano, H., Misumi, I., Miyamoto, S., Kojima, S., Sakamoto, T., Yoshimura, M., Ogawa, H. 2005; 44 (5): 453-457

    Abstract

    A 71-year-old woman was admitted for paralysis on the left side of her body. She developed dyspnea and hypoxemia after admission. Although pulmonary embolism was suspected, hypoxemia and dyspnea occurred repeatedly in spite of anticoagulation therapy. Transesophageal echocardiography revealed a patent foramen ovale (PFO), an atrial septal aneurysm (ASA), and a right-to-left shunt that appeared in an upright position. She was diagnosed with platypnea-orthodeoxia syndrome. Moreover, cardiac catheterization showed congenital anomalies, such as unroofed coronary sinus, partial anomalous pulmonary venous return and persistent left superior vena cava. Simple surgical closure of the ASA and PFO improved all of her symptoms.

    View details for Web of Science ID 000229852100018

    View details for PubMedID 15942093

  • Sensorineural hearing loss combined with Takayasu's arteritis INTERNAL MEDICINE Maruyoshi, H., Toyama, K., Kojima, S., Kawano, H., Ogata, N., Miyamoto, S., Sakamoto, T., Yoshimura, M., Ogawa, H. 2005; 44 (2): 124-128

    Abstract

    A 49-year-old woman complained of hearing loss and diminution of left radial arterial pulsation. She had been diagnosed with sudden deafness and treated with corticosteroids. Her audibility deteriorated again after the cessation of the therapy. Angiograms showed stenosis in the bilateral carotid arteries, the left vertebral artery, the left subclavian artery, and the pulmonary arteries. She was diagnosed with Takayasu's arteritis. After steroid therapy was restarted, there were improvements in her audibility, radial arterial pulsation, and levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, and gamma-globulin), fibrinogen, interleukin-6, and RANTES (regulated on activation, normal T cell expressed and secreted).

    View details for Web of Science ID 000227135800009

    View details for PubMedID 15750272

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