Daihiko Hakuno

National Defense Medical College, Tokorozawa, Saitama, Japan

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Publications (36)209.52 Total impact

  • Daihiko Hakuno · Sarasa Isobe · Nobuyuki Masaki · Takeshi Adachi
    Circulation Journal 06/2015; 79(9). DOI:10.1253/circj.CJ-14-1246 · 3.94 Impact Factor
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    Daihiko Hakuno · Yasuhito Hamba · Takumi Toya · Takeshi Adachi
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    ABSTRACT: The heart has close interactions with other organs' functions and concomitant systemic factors such as oxidative stress, nitric oxide (NO), inflammation, and nutrition in systolic heart failure (HF). Recently, plasma amino acid (AA) profiling as a systemic metabolic indicator has attracted considerable attention in predicting the future risk of human cardiometabolic diseases, but it has been scarcely studied in HF. Thirty-eight stable but greater than New York Heart Association class II symptomatic patients with left ventricular (LV) ejection fraction <45% and 33 asymptomatic individuals with normal B-type natriuretic peptide (BNP) value were registered as the HF and control groups, respectively. We analyzed fasting plasma concentrations of 41 AAs using high-performance liquid chromatography, serum NO metabolite concentration, hydroperoxide and high-sensitivity C-reactive protein measurements, echocardiography, and flow-mediated dilatation. We found that 17 AAs and two ratios significantly changed in the HF group compared with those in the control group (p < 0.05). In the HF group, subsequent univariate and stepwise multivariate analyses with clinical variables revealed that Fischer ratio and five specific AAs, ie, monoethanolamine, methionine, tyrosine, 1-methylhistidine, and histidine have significant correlation with BNP, LV ejection fraction, LV end-diastolic volume index, inferior vena cava diameter, the ratio of early diastolic velocity of the mitral inflow to mitral annulus, and BNP, respectively (p < 0.05). Interestingly, further exploratory factor analysis categorized these AAs into hepatic-related (monoethanolamine, tyrosine, and Fischer ratio) and skeletal muscle-related (histidine, methionine, and 1-methylhistidine) components. Some categorized AAs showed unique correlations with concomitant factors: monoethanolamine, tyrosine, and Fischer ratio with serum NO concentration; histidine with serum albumin; and 1-methylhistidine with flow-mediated dilatation (p < 0.05). Plasma AA profiling identified correlations of specific AAs with cardiac function and concomitant factors, highlighting the cardio-hepatic-skeletal muscle axis in patients with systolic HF.
    PLoS ONE 02/2015; 10(2):e0117325. DOI:10.1371/journal.pone.0117325 · 3.23 Impact Factor
  • European Heart Journal – Cardiovascular Imaging 10/2014; 16(2). DOI:10.1093/ehjci/jeu205 · 2.65 Impact Factor
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    ABSTRACT: A metabolizing enzyme arginase can decrease nitric oxide (NO) production by competing with NO synthase for arginine as a substrate, but its pathophysiological role in heart failure remains unknown. We aimed to investigate the effect of pharmacological inhibition of arginase on left ventricular function in doxorubicin-induced cardiomyopathy in mice. Doxorubicin administration for 5 weeks significantly increased protein expression levels or activity of arginase in the lungs and liver, and caused moderate increase in arginase 2 expression in the aorta. In the lungs, accumulated interstitial cells strongly expressed both arginase 1 and arginase 2 by doxorubicin administration. Echocardiography revealed that administration of a potent, reversible arginase inhibitor N-omega-hydroxy-nor-l-arginine completely reversed doxorubicin-induced decrease in the ejection fraction, in parallel with expression levels of BNP mRNA, without affecting apoptosis, hypertrophy, fibrosis, or macrophage infiltration in the left ventricle. Arginase inhibition reversibly lowered systolic blood pressure, and importantly, it recovered doxorubicin-induced decline in NO concentration in the serum, lungs, and aorta. Furthermore, arginase inhibition stimulated NO secretion from aortic endothelial cells and peritoneal macrophages in vitro. In conclusion, pharmacological inhibition of arginase augmented NO concentration in the serum, lungs, and aorta, promoted NO-mediated decrease in afterload for left ventricle, and facilitated left ventricular systolic function in doxorubicin-induced cardiomyopathy in mice.
    09/2014; 2(9). DOI:10.14814/phy2.12130
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    ABSTRACT: Background Endothelial dysfunction causes vasomotor dysregulation and vascular stiffening in addition to structural changes. By influencing NO synthesis, deficiency of l-arginine relative to asymmetric dimethylarginine (ADMA), which is an l-arginine derivative that acts as a competitive NO synthase inhibitor, may lead to the promotion of arterial stiffness. This study investigated the relationship between the l-arginine/ADMA ratio and brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness. Methods and results This cross-sectional study enrolled 74 patients (62 men, 12 women; mean age, 67 ± 10 years) undergoing elective coronary angiography. A total of 54 (73%) patients had coronary artery disease. Serum l-arginine and ADMA were measured by high-performance liquid chromatography with fluorescence detection. The ratio of l-arginine to ADMA and the serum l-arginine level was associated with baPWV in univariate regression analysis (l-arginine/ADMA ratio: β = −0.323, p = 0.005; l-arginine: β = −0.247, p = 0.034). In addition, baPWV was related to blood hemoglobin concentration, hematocrit, brain natriuretic peptide level, symmetric dimethylarginine, renal function, blood pressure, and heart rate. In multivariate analysis, the l-arginine/ADMA ratio was a significant predictor of baPWV (β = −0.310, p < 0.001). In subgroup analyses, the l-arginine/ADMA ratio was associated with baPWV in elderly patients (n = 46, β = −0.359, p = 0.004), and in younger patients (n = 28, β = −0.412, p = 0.006). Conclusion A low l-arginine/ADMA ratio may be associated with high baPWV in patients undergoing coronary angiography.
    Journal of Cardiology 07/2014; 65(4). DOI:10.1016/j.jjcc.2014.06.005 · 2.78 Impact Factor
  • Toyokazu Kimura · Daihiko Hakuno · Susumu Isoda · Takeshi Adachi
    Circulation Journal 06/2014; 78(10). DOI:10.1253/circj.CJ-14-0394 · 3.94 Impact Factor
  • Takafumi Nishida · Daihiko Hakuno
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    ABSTRACT: A 68-year-old man who had Behcet's disease with a 30-year history of oral and genital ulcers and erythema nodosum presented with progressive leg edema and dyspnea. The physical examination revealed varices of the chest and abdominal wall. A 68-year-old man who had Behcet's disease with a 30-year history of oral and genital ulcers and erythema nodosum presented with progressive leg edema and dyspnea. The physical examination revealed varices of the chest and abdominal wall (Panel A), caused by collateral circulation associated with obstruction of the superior vena cava (SVC). Chest computed tomography (CT) showed SVC obstruction (Panel B, arrows) and dilatation of the inferior vena cava (arrowhead). Endocardial calcification on the midlateral and apical wall (Panel C, arrow) was more extensive than that seen on imaging performed 11 years earlier (Panel D, arrow), and there was increased ...
    New England Journal of Medicine 11/2013; 369(21):e28. DOI:10.1056/NEJMicm1305579 · 55.87 Impact Factor
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    ABSTRACT: Insulin signaling comprises 2 major cascades: the insulin receptor substrate/phosphatidylinositol 3'-kinase/protein kinase B and Ras/Raf/mitogen-activated protein kinase/kinase/ERK pathways. While many studies on the tissue-specific effects of the insulin receptor substrate/phosphatidylinositol 3' -kinase/protein kinase B pathway have been conducted, the role of the other cascade in tissue-specific insulin resistance has not been investigated. High glucose/fatty acid toxicity, inflammation, and oxidative stress, all of which are associated with insulin resistance, can activate ERK. The liver plays a central role in metabolism, and hepatosteatosis is associated with vascular diseases. The aim of study was to elucidate the role of hepatic ERK2 in hepatosteatosis, metabolic remodeling, and endothelial dysfunction. We created liver-specific ERK2 knockout mice and fed them with a high-fat/high-sucrose diet for 20 weeks. The high-fat/high-sucrose diet-fed liver-specific ERK2 knockout mice exhibited a marked deterioration in hepatosteatosis and metabolic remodeling represented by impairment of glucose tolerance and decreased insulin sensitivity without changes in body weight, blood pressure, and serum cholesterol/triglyceride levels. In the mice, endoplasmic reticulum stress was induced together with decreased mRNA and protein expressions of hepatic sarco/endoplasmic reticulum Ca(2+)-ATPase 2. In a hepatoma cell line, inhibition of ERK activation- induced endoplasmic reticulum stress only in the presence of palmitate. Vascular reactive oxygen species were elevated with upregulation of nicotinamide adenine dinucleotide phosphate oxidase1 (Nox1) and Nox4 and decreased phosphorylation of endothelial nitric oxide synthase, which resulted in the remarkable endothelial dysfunction in high-fat/high-sucrose diet-fed liver-specific ERK2 knockout mice. Hepatic ERK2 suppresses endoplasmic reticulum stress and hepatosteatosis in vivo, which results in protection from vascular oxidative stress and endothelial dysfunction. These findings demonstrate a novel role of hepatic ERK2 in obese-induced insulin resistance in the protection from hepatovascular metabolic remodeling and vascular diseases.
    Journal of the American Heart Association 07/2013; 2(4):e000361. DOI:10.1161/JAHA.113.000361 · 4.31 Impact Factor
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    ABSTRACT: The patient was a 78-year-old man. In August 2007, he underwent catheter ablation for atrial fibrillation after taking bepridil for 3 weeks. Soon after the ablation, he experienced frequent atrial extrasystoles and began taking bepridil again on the day he left the hospital. Six days after discharge, he was readmitted to our hospital with dyspnea and was diagnosed with acute heart failure. The patient had no recurrence of atrial fibrillation, so the administration of bepridil was stopped. His dyspnea was eased using standard therapy for heart failure and he was discharged from our hospital. In March 2011, he had a recurrence of atrial fibrillation and was readmitted to our hospital. The administration of bepridil was initiated to defibrillate the atrial fibrillation. Although bepridil stopped the atrial fibrillation by the third day, he presented with dyspnea and fever on the fourth day. A chest radiograph showed bilateral interstitial patterns that radiated from the pulmonary hilum. He was treated for acute heart failure and bacterial pneumonia, but this was ineffective. We suspected that the interstitial pneumonia was caused by bepridil. Corticosteroid therapy dramatically improved his symptoms. This was a rare case of acute drug-induced interstitial pneumonia caused by repeated exposure to bepridil.
    Journal of Arrhythmia 02/2013; 29(1):39–42. DOI:10.1016/j.joa.2012.09.005
  • Journal of Cardiac Failure 10/2012; 18(10):S189. DOI:10.1016/j.cardfail.2012.08.347 · 3.05 Impact Factor
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    JACC. Cardiovascular imaging 05/2012; 5(5):570-1. DOI:10.1016/j.jcmg.2012.01.015 · 7.19 Impact Factor
  • Daihiko Hakuno · Takumi Toya · Takeshi Adachi
    Journal of Echocardiography 03/2012; 11(1). DOI:10.1007/s12574-012-0155-8
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    ABSTRACT: The anti-oxidant enzyme copper/zinc superoxide dismutase (CuZnSOD) metabolizes superoxide anion (O(2)(-)) in vascular cells. However, the role of CuZnSOD in vascular injury remains poorly understood. Using CuZnSOD-deficient (CuZnSOD(-/-)) mice and wild-type (WT) mice, we investigated morphometric changes and the role of O(2)(-) in vascular remodeling after femoral artery injury induced by an external vascular cuff model. Three days post-injury, inflammatory cell infiltration increased significantly. Moreover, the percent positive area of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in media were higher in CuZnSOD(-/-) mice than in WT mice (TNF-α: 34.8±8.4% versus 18.8±5.6%, p < 0.05, ICAM-1: 29.6±6.5% versus 11.0±2.8%, p < 0.05, VCAM-1: 23.5±7.5% versus 3.7±1.1%, p < 0.05). mRNA expression of iNOS was markedly increased in CuZnSOD(-/-) mice with cuff injury. Dihydroethidine staining revealed increased levels of vascular O(2)(-) in media from CuZnSOD(-/-) mice. Although neointimal formation remained unchanged, 14 days postinjury, we observed degeneration of the media, and the media/vessel wall ratio increased in CuZnSOD(-/-) mice (40.4±2.1% versus 26.8±1.4%, p < 0.05). Furthermore, SMemb/MHC-B-stained lesions increased markedly in CuZnSOD(-/-) mice. CuZnSOD-deficiency promoted inflammation, expressed adhesion molecules, and altered the structure of the media post-injury. Our results suggest that O(2)(-) participates importantly in the progression of early stage vascular inflammation, resulting in vascular remodeling in media but not neointimal formation, post-injury.
    Journal of atherosclerosis and thrombosis 09/2011; 18(11):1009-17. DOI:10.5551/jat.9324 · 2.73 Impact Factor
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    ABSTRACT: The aging of populations worldwide and the habitual consumption of food high in calories and cholesterol have led to recent increases in morbidity from calcific aortic valve disease. At the same time, rupture of the chordae tendineae cordis, which is a component of the mitral valve complex, is one of the major causes of mitral regurgitation. Surgery is the basis of treatment for these diseases, and little is known about their causes and mechanisms. A balance of angiogenetic and angioinhibitory factors is crucial for normal development and homeostasis of many organs. Although the heart is a vascular-rich organ, most of the cardiac valve complex is avascular like cartilage and tendons. Our studies have focused on the role of angiogenetic factors expressed in the cartilage and tendons in cardiac valve homeostasis. Recently, we found that chondromodulin-I, tenomodulin, and periostin play essential roles in degeneration and/or rupture of the cardiac valve complex by controlling angiogenesis and matrix metalloproteinase production. Here, we review the mechanistic insights provided by these studies and the proposed roles of angiogenetic factors in cardiac valve homeostasis and disease.
    Journal of Cardiovascular Translational Research 08/2011; 4(6):727-40. DOI:10.1007/s12265-011-9317-8 · 3.02 Impact Factor
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    ABSTRACT: Valvular heart disease (VHD) is the term given to any disease process involving one or more of the heart valves. The condition can be congenital or acquired, for example as a result of atherosclerosis or rheumatic fever. Despite its clinical importance, the molecular mechanisms underlying VHD remain unknown. We investigated the pathophysiologic role and molecular mechanism of periostin, a protein that plays critical roles in cardiac valve development, in degenerative VHD. Unexpectedly, we found that periostin levels were drastically increased in infiltrated inflammatory cells and myofibroblasts in areas of angiogenesis in human atherosclerotic and rheumatic VHD, whereas periostin was localized to the subendothelial layer in normal valves. The expression patterns of periostin and chondromodulin I, an angioinhibitory factor that maintains cardiac valvular function, were mutually exclusive. In WT mice, a high-fat diet markedly increased aortic valve thickening, annular fibrosis, and MMP-2 and MMP-13 expression levels, concomitant with increased periostin expression; these changes were attenuated in periostin-knockout mice. In vitro and ex vivo studies revealed that periostin promoted tube formation and mobilization of ECs. Furthermore, periostin prominently increased MMP secretion from cultured valvular interstitial cells, ECs, and macrophages in a cell type-specific manner. These findings indicate that, in contrast to chondromodulin I, periostin plays an essential role in the progression of cardiac valve complex degeneration by inducing angiogenesis and MMP production.
    The Journal of clinical investigation 07/2010; 120(7):2292-306. DOI:10.1172/JCI40973 · 13.22 Impact Factor
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    ABSTRACT: Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture. We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC, where abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, but not in the normal or nonruptured area. In anesthetized open-chest dogs, the tenomodulin layer of tricuspid CTC was surgically filed, and immunohistological analysis was performed after several months. This intervention gradually caused angiogenesis and expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core collagen layer in a time-dependent manner. These findings provide evidence that tenomodulin is expressed universally in normal CTC in a concentric pattern and that local absence of tenomodulin, angiogenesis, and matrix metalloproteinase activation are associated with CTC rupture.
    Circulation 11/2008; 118(17):1737-47. DOI:10.1161/CIRCULATIONAHA.108.780031 · 14.43 Impact Factor
  • Naritaka Kimura · Daihiko Hakuno · Ryohei Yozu · Keiichi Fukuda
    Journal of Molecular and Cellular Cardiology 10/2008; 45(4). DOI:10.1016/j.yjmcc.2008.09.677 · 4.66 Impact Factor
  • Journal of Molecular and Cellular Cardiology 10/2008; 45(4). DOI:10.1016/j.yjmcc.2008.09.615 · 4.66 Impact Factor

Publication Stats

1k Citations
209.52 Total Impact Points


  • 2010–2014
    • National Defense Medical College
      • • Division of Cardiology
      • • Department of Internal Medicine
      Tokorozawa, Saitama, Japan
  • 2000–2008
    • Keio University
      • • School of Medicine
      • • Department of Internal Medicine
      Edo, Tōkyō, Japan