平出　貴裕 （ヒライデ　タカヒロ）

Hiraide, Takahiro

写真a

所属（所属キャンパス）

医学部 内科学教室（循環器） （信濃町）

職名

助教（有期）
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  • 2016年04月
    -
    継続中

    慶應義塾大学医学部内科学教室循環器内科

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学歴 【 表示 ／ 非表示 】

  • 2006年04月
    -
    2012年03月

    慶應義塾大学医学部

    大学, 卒業

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  • ライフサイエンス / 循環器内科学

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  • 肺高血圧症

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  • MRP1-Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis After Ischemia-Reperfusion

    Ichihara G., Katsumata Y., Sugiura Y., Matsuoka Y., Maeda R., Endo J., Anzai A., Shirakawa K., Moriyama H., Kitakata H., Hiraide T., Goto S., Ko S., Iwasawa Y., Sugai K., Daigo K., Goto S., Sato K., Yamada K.I., Suematsu M., Ieda M., Sano M.

    Circulation Research （Circulation Research）  133 （ 10 ） 861 - 876 2023年10月

    ISSN  00097330

    　概要を見る

    BACKGROUND: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. METHODS: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain. RESULTS: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury. CONCLUSIONS: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.

  • Long-term Follow-up of Qing-Dai–Induced Pulmonary Arterial Hypertension: A Case Series

    Matsushima T., Hiraide T., Momoi M., Shinya Y., Anzai A., Inami T., Fukuda K., Kataoka M., Ieda M.

    CJC Open （CJC Open）  5 （ 10 ） 779 - 783 2023年10月

  • De-escalation of Oxygen Therapy and Medication in Patients With Chronic Thromboembolic Pulmonary Hypertension After Balloon Pulmonary Angioplasty

    Kimura M., Kohno T., Shinya Y., Hiraide T., Moriyama H., Endo J., Murata M., Fukuda K.

    Canadian Journal of Cardiology （Canadian Journal of Cardiology）  39 （ 5 ） 637 - 645 2023年05月

    ISSN  0828282X

    　概要を見る

    Background: There is no consensus on the adjustment of home oxygen therapy (HOT) and pulmonary hypertension (PH)-specific medications after balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to examine the status of de-escalation and discontinuation of HOT and PH-specific medications post-BPA and clarify its effect on hemodynamics, biomarkers, and long-term outcomes. Methods: From November 2012 to May 2018, 135 consecutive patients with CTEPH who underwent BPA at a single university hospital were enrolled (age, 63.5 ± 13.5 years; World Health Organization functional class (WHO-FC) II, III, IV; 34, 92, 9). Results: The mean pulmonary arterial pressure decreased from 37.7 ± 11.3 to 20.4 ± 5.1 mm Hg 1 year post-BPA (P < 0.01). The proportion of patients who required HOT and combination medical therapy (≥ 2 PH-specific medications) decreased 1 year post-BPA (from 58.5% to 7.4% and from 40.0% to 10.4%, respectively). Baseline factors influencing the requirement of HOT and combination medical therapy post-BPA were almost identical (ie, lower exercise capacity and pulmonary diffusion capacity and worse hemodynamics). Regardless of their discontinuation, the improved hemodynamics, functional capacity (WHO-FC), and biomarkers (B-type natriuretic peptide and high-sensitivity troponin T) were almost maintained, and no adverse 1-year clinical outcomes (all-cause death and PH-related hospitalization) were observed. Conclusions: Most patients with CTEPH discontinued HOT and PH-specific combination medical therapy post-BPA, which was not associated with the deterioration of hemodynamics, functional capacity, or biomarkers. No long-term adverse outcomes were observed.

  • Genetic Backgrounds Associated With Stent Thrombosis: A Pilot Study From a Percutaneous Coronary Intervention Registry

    Shoji S., Sawano M., Inohara T., Hiraide T., Ueda I., Suzuki M., Noma S., Fukuda K., Kohsaka S.

    JACC: Advances （JACC: Advances）  2 （ 1 ）  2023年01月

    　概要を見る

    Background: Stent thrombosis (ST) is a rare, yet devastating, complication following percutaneous coronary intervention (PCI), with poorly understood pathophysiologic characteristics and genetic backgrounds. Objectives: The authors performed a genome-wide association study to identify the common genetic loci associated with early stent thrombosis (EST) and late/very late ST (LST/VLST) in a contemporary Japanese multicenter PCI registry. Methods: Among 8,642 PCI patients included in the registry, 42 who experienced stent thrombosis [EST (n = 15) and LST/VLST (n = 27)] were included (mean age, 67.6 ± 10.8 years; and 88.1% men). We conducted a genome-wide association study using the BioBank Japan patient population as the control (control #1: acute coronary syndrome [n = 29,542] and control #2: effort angina [n = 8,900]) to identify significant single nucleotide polymorphisms (SNPs) and evaluate the performance of polygenic risk scores (PRSs) for predicting these conditions. Results: We compared patients with EST with controls #1 and #2 and identified SNPs (rs565401593 and rs561634568) in NSD1, and patients with LST/VLST with controls #1 and #2 and identified SNPs (rs532623294 and rs199546342) in GRIN2A. PRS for LST/VLST showed high predictive performance (area under the curve 0.83 [95% CI: 0.76-0.89] and 0.83 [95% CI: 0.77-0.89]), whereas PRS for EST showed modest predictive performance (area under the curve 0.71 [95% CI: 0.58-0.85] and 0.72 [95% CI: 0.58-0.85]). Conclusions: We identified different genetic predispositions between EST and LST/VLST and demonstrated that the incorporation of PRS may aid in risk prediction of this highly fatal event.

  • Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

    Moriyama H., Endo J., Kataoka M., Shimanaka Y., Kono N., Sugiura Y., Goto S., Kitakata H., Hiraide T., Yoshida N., Isobe S., Yamamoto T., Shirakawa K., Anzai A., Katsumata Y., Suematsu M., Kosaki K., Fukuda K., Arai H., Sano M.

    Nature Communications （Nature Communications）  13 （ 1 ）  2022年12月

    　概要を見る

    Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-β signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.

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  • RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies

    Hiraide T., Suzuki H., Momoi M., Shinya Y., Fukuda K., Kosaki K., Kataoka M.

    Life （Life）  12 （ 4 ）  2022年04月

    　概要を見る

    The ring finger protein 213 gene (RNF213) encodes a 590 kDa protein that is thought to be involved in angiogenesis. This gene was first recognized as a vasculopathy-susceptibility locus through genome-wide association studies undertaken in a Japanese population, demonstrating that heterozygotes for RNF213 p.Arg4810Lys (c.14429G>A, rs112735431) had a greatly increased risk of moyamoya disease. The association of RNF213 p.Arg4810Lys as a susceptibility variant of moyamoya disease was reproduced in Korean and Chinese individuals and, later, in Caucasians. Variants of the RNF213 gene have been linked to a number of vascular diseases such as moyamoya disease, intracranial major artery stenosis, pulmonary arterial hypertension, and peripheral pulmonary artery stenosis, and have also been associated with co-occurrent diseases and vascular disease in different organs. Based on the findings that we have reported to date, our paper proposes a new concept of “RNF213-associated vascular disease” to unify these conditions with the aim of capturing patients with multiple diseases but with a common genetic background. This concept will be highly desirable for clarifying all of the diseases in the RNF213-associated vascular disease category by means of global epidemiological investigations because of the possibility of such diseases appearing asymptomatically in some patients.

  • Pulmonary arterial hypertension caused by AhR signal activation protecting against colitis

    Hiraide T., Teratani T., Uemura S., Yoshimatsu Y., Naganuma M., Shinya Y., Momoi M., Kobayashi E., Hakamata Y., Fukuda K., Kanai T., Kataoka M.

    American Journal of Respiratory and Critical Care Medicine （American Journal of Respiratory and Critical Care Medicine）  203 （ 3 ） 385 - 388 2021年02月

    ISSN  1073449X

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研究発表 【 表示 ／ 非表示 】

  • Incidence and Predictors of Procedure-Related Coronary Artery Dissection in Percutaneous Coronary Intervention: A Report from a Multicenter Contemporary Registry

    平出 貴裕

    European Society of Cardiology Congress, 

    2017年08月
    , 

    ポスター発表

  • 特発性肺高血圧症におけるBMPR2遺伝子異常と右室機能の関連について

    平出 貴裕

    第2回日本肺高血圧学会, 

    2017年06月
    , 

    口頭発表（一般）

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  • 炎症性ケモカインに着目した難治性全身血管病の病態解明

    2023年04月
    -
    2025年03月

    平出 貴裕, 若手研究, 補助金,  研究代表者

  • 日本人特有のゲノム変異に基づく難治性血管病の病態解明と新規創薬ターゲットの検索

    2021年04月
    -
    2023年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 平出 貴裕, 若手研究, 補助金,  研究代表者

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