APE1 as a diagnostic and therapeutic target molecule of viral myocardial damage

• Project/Area Number: 21K08021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Asahikawa Medical College
• Principal Investigator: 長谷部 直幸 旭川医科大学, 医学部, 名誉教授 (30192272)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: APE1 / ウイルス性心筋炎 / HFrEF / バイオマーカー / アポトーシス / ウイルス感染庄 / 心筋傷害

Outline of Research at the Start

2020年秋現在、COVID-19パンデミックの猛威は、終息の気配すら見えない。
本研究では、ウイルス性心筋炎の病態重症化機序とAPE1の作用機序の共通性から、以下の二つの仮説を検証する。
①APE1がウイルス性心筋傷害の発生・重症化を早期に検出する新たなバイオマーカーとなり得る。
②APE１がウイルス性心筋傷害の心筋組織修復・心機能回復の新たな治療標的となり得る。
この検証のためウイルス性心筋傷害マウスモデルを用い、経時的解析によりウイルス性心筋傷害の診断・治療両面における新たな標的分子としてのAPE1の可能性を明らかにするものである。

Outline of Annual Research Achievements

ウイルス性心筋炎による心筋傷害および心機能障害がCOVID-19パンデミックにより改めて注目されている。ウイルス性心筋炎のマウスモデルにおいては、心筋傷害の程度に依存して心筋APE1発現量の増加することが先行研究で明らかにされたことから、心筋傷害のバイオマーカーとしてのAPE1の診断的意義が想定された。同じく先行研究においてサイトカインストーム状態におけるAPE1の組織障害修飾作用が検出されたことから、APE1を介する炎症～リモデリング促進機序の制御がウイルス性心筋炎における本質的な治療標的となる可能性も示唆された。ウイルス性心筋炎におけるDNA二本鎖切断によるアポトーシスの誘導やROS産生による酸化ストレスの亢進は心筋傷害の主要な機序であり、APE1作用機序と多くの共通性が存在することから、ウイルス性心筋炎においてAPE1が心筋傷害の発生・重症化を早期に検出し得る新たなバイオマーカーとなり得る診断的意義とAPE１がウイルス性心筋傷害の心筋組織修復および心機能回復を促進するための新たな治療標的分子となり得る治療的意義の両側面から検討を進めた。Coxsackievirus B3 (CVB3)のH3系（CVB3-H3）を標的として、BALB/cマウスへのCVB3-H3の多段階用量適用下では、APE1 (ELISA)の経時的増加が認められ、心筋トロポニンT/I、BNP等の経時的変動との比較から特異的バイオマーカーとしての意義が示唆された。またAPE1の心筋導入により特に虚血領域でのアポトーシス抑制を介する心筋組織障害の軽減と心リモデリング抑制効果が示唆され、新たな治療標的分子となる可能性が示唆された。本研究結果を前提として、広くウイルス性心筋炎による心筋傷害および心機能障害における新たな診断・治療標的分子としてのAPE1の意義を確立するための研究を進める予定である。

Research Products

• [Journal Article] Uninterrupted medical care against disasters and pandemics (2023)
  • Author(s): Hasebe Tomomi、Hasebe Naoyuki
  • Journal Title: Hypertension Research Volume: 47 Issue: 2 Pages: 556-558
  • DOI: 10.1038/s41440-023-01524-3
  • Peer Reviewed
• [Journal Article] Real‐world trends in pre‐dialysis blood pressure levels of patients undergoing dialysis in Japan using a web‐based national database (2023)
  • Author(s): Sakuma Hirofumi、Matsuki Motoki、Hasebe Naoyuki、Nakagawa Naoki
  • Journal Title: The Journal of Clinical Hypertension Volume: 25 Issue: 12 Pages: 1163-1171
  • DOI: 10.1111/jch.14736
  • Peer Reviewed
• [Journal Article] Regional variation in pre-dialysis blood pressure and its association with cardiovascular mortality rates in Japanese patients undergoing dialysis (2023)
  • Author(s): Sakuma Hirofumi、Ikeda Minori、Nakao Shiori、Suetsugu Reina、Matsuki Motoki、Hasebe Naoyuki、Nakagawa Naoki
  • Journal Title: Hypertension Research Volume: 47 Issue: 1 Pages: 102-111
  • DOI: 10.1038/s41440-023-01415-7
  • Peer Reviewed
• [Journal Article] NG2-positive pericytes regulate homeostatic maintenance of slow-type skeletal muscle with rapid myonuclear turnover (2023)
  • Author(s): Tatsukawa Takamitsu、Kano Kohei、Nakajima Kei-ichi、Yazawa Takashi、Eguchi Ryoji、Kabara Maki、Horiuchi Kiwamu、Hayasaka Taiki、Matsuo Risa、Hasebe Naoyuki、Azuma Nobuyoshi、Kawabe Jun-ichi
  • Journal Title: Stem Cell Research & Therapy Volume: 14 Issue: 1 Pages: 205-205
  • DOI: 10.1186/s13287-023-03433-1
  • Peer Reviewed / Open Access
• [Journal Article] Anticoagulant therapy and home blood pressure-associated risk for stroke/bleeding events in elderly patients with non-valvular atrial fibrillation: the sub-cohort study of ANAFIE registry (2023)
  • Author(s): Kario Kazuomi、Hasebe Naoyuki、Okumura Ken、Yamashita Takeshi、et. al.
  • Journal Title: Hypertension Research Volume: 46 Issue: 12 Pages: 2575-2582
  • DOI: 10.1038/s41440-023-01361-4
  • Peer Reviewed
• [Journal Article] A big issue on a small island?Obesity increases hypertension (2023)
  • Author(s): Hasebe Tomomi、Hasebe Naoyuki
  • Journal Title: Hypertension Research Volume: 46 Issue: 9 Pages: 2237-2239
  • DOI: 10.1038/s41440-023-01343-6
  • Peer Reviewed
• [Journal Article] NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: A case report and literature review (2023)
  • Author(s): Katayama Takayuki、Takahashi Kae、Yahara Osamu、Sawada Jun、Ishida Ken-ichi、Asanome Asuka、Endo Hisako、Saito Tsukasa、Hasebe Naoyuki、Kishibe Mari、Kanno Harumi、Ishiko Satoshi、Sone Jun
  • Journal Title: Medicine Volume: 102 Issue: 19 Pages: e33789-e33789
  • DOI: 10.1097/md.0000000000033789
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 mediates the late phase of ischemic preconditioning in the heart via its receptor subtype EP4 (2022)
  • Author(s): Kanno Takayasu、Nakagawa Naoki、Aonuma Tatsuya、Kawabe Jun-ichi、Yuhki Koh-ichi、Takehara Naofumi、Hasebe Naoyuki、Ushikubi Fumitaka
  • Journal Title: Heart and Vessels Volume: 38 Issue: 4 Pages: 606-613
  • DOI: 10.1007/s00380-022-02219-4
  • Peer Reviewed / Open Access
• [Journal Article] Ninjurin1 Deletion in NG2-Positive Pericytes Prevents Microvessel Maturation and Delays Wound Healing (2022)
  • Author(s): Matsuo Risa、Kishibe Mari、Horiuchi Kiwamu、Kano Kohei、Tatsukawa Takamitsu、Hayasaka Taiki、Kabara Maki、Iinuma Shin、Eguchi Ryoji、Igawa Satomi、Hasebe Naoyuki、Ishida-Yamamoto Akemi、Kawabe Jun-ichi
  • Journal Title: JID Innovations Volume: 2 Issue: 6 Pages: 100141-100141
  • DOI: 10.1016/j.xjidi.2022.100141
  • Peer Reviewed / Open Access
• [Journal Article] Home Blood Pressure Can Predict the Risk for Stroke/Bleeding Events in Elderly Patients With Nonvalvular Atrial Fibrillation From the ANAFIE Registry (2022)
  • Author(s): Kario Kazuomi、Hasebe Naoyuki、Okumura Ken、et al
  • Journal Title: Hypertension Volume: 79 Issue: 12 Pages: 2696-2705
  • DOI: 10.1161/hypertensionaha.122.19810
  • Peer Reviewed / Open Access
• [Journal Article] Corrigendum to ‘Prospective observational study in elderly patients with non-valvular atrial fibrillation: Rationale and design of the All Nippon AF In the Elderly (ANAFIE) Registry’ [Journal of Cardiology 72 (2018) 300?306] (2022)
  • Author(s): Inoue Hiroshi、Yamashita Takeshi、Akao Masaharu、et al
  • Journal Title: Journal of Cardiology Volume: 80 Issue: 4 Pages: 375-376
  • DOI: 10.1016/j.jjcc.2022.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease (2022)
  • Author(s): Naito Ryo、Miyauchi Katsumi、Yasuda Satoshi、ichishita Ichiro、Fujikura Hisanori、Momomura Shinichi、uichi、Kagiyama Shuntaro、Teragawa Hiroki、Yuge Masaru、ihiko、Horiuchi Masataka、Nagano Toshihiko、Takaishi Atsushi、、Nakamura Yuichi、Komaru Tatsuya、Hosokawa Takeshi、et al AFIRE Investigators
  • Journal Title: JAMA Cardiology Volume: 7 Issue: 8 Pages: 787-787
  • DOI: 10.1001/jamacardio.2022.1561
  • Peer Reviewed / Open Access
• [Journal Article] Impact of risk factors related to metabolic syndrome on acute myocardial infarction in younger patients (2022)
  • Author(s): Hasebe Tomomi、Hasebe Naoyuki
  • Journal Title: Hypertension Research Volume: 45 Issue: 9 Pages: 1447-1458
  • DOI: 10.1038/s41440-022-00951-y
  • Peer Reviewed / Open Access
• [Journal Article] Intensive or standard blood pressure control in patients with a history of ischemic stroke: RESPECT post hoc analysis (2022)
  • Author(s): Kazuo Kitagawa, Hisatomi Arima, et al
  • Journal Title: Hypertens Res . Volume: 45(4) Issue: 4 Pages: 591-601
  • DOI: 10.1038/s41440-022-00862-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characteristics of Neurological Symptoms in Adult Japanese Patients with Fabry Disease (2021)
  • Author(s): Sawada Jun、Nakagawa Naoki、Kano Kohei、Saito Tsukasa、Katayama Takayuki、Sawada Takaaki、Momosaki Ken、Nakamura Kimitoshi、Hasebe Naoyuki
  • Journal Title: Internal Medicine Volume: 60 Issue: 12 Pages: 1819-1826
  • DOI: 10.2169/internalmedicine.6420-20
  • NAID: 130008052662
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-06-15
  • Peer Reviewed / Open Access
• [Journal Article] <i>Erratum for</i> Antimitochondrial Antibody-associated Myopathy with Slowly Progressive Cardiac Dysfunction (2021)
  • Author(s): Takahashi Fumihiko、Sawada Jun、Minoshima Akiho、Sakamoto Naka、Ono Toshiyuki、Akasaka Kazumi、Takei Hidehiro、Nishino Ichizo、Hasebe Naoyuki
  • Journal Title: Internal Medicine Volume: 60 Issue: 7 Pages: 1141-1141
  • DOI: 10.2169/internalmedicine.E003-20
  • NAID: 130008014385
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-04-01
  • Peer Reviewed
• [Journal Article] Acute Myocardial Infarction in a 17-year-old High-school Girl (2021)
  • Author(s): Kawaguchi S, Hasebe T, Ohta H, Kikuchi A, Asanome A, Nishiura T, Sakamoto N, Tanabe Y, Takeuchi T, Sato N, Kawamura Y, Hasebe N.
  • Journal Title: Internal Medicine Volume: 60 Issue: 2 Pages: 259-263
  • DOI: 10.2169/internalmedicine.5437-20
  • NAID: 130007968963
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-01-15
  • Peer Reviewed / Open Access
• [Journal Article] Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy (2021)
  • Author(s): Katayama Takayuki、Sawada Jun、Takahashi Kae、Yahara Osamu、Hasebe Naoyuki
  • Journal Title: Alzheimer's Research Therapy Volume: 13 Issue: 1 Pages: 2330-2340
  • DOI: 10.1186/s13195-021-00907-3
  • Peer Reviewed
• [Journal Article] Utility of Geriatric Nutritional Risk Index in Patients with Chronic Kidney Disease: A Mini-Review (2021)
  • Author(s): Nakagawa Naoki、Maruyama Keisuke、Hasebe Naoyuki
  • Journal Title: Nutrients Volume: 13 Issue: 11 Pages: 3688-3688
  • DOI: 10.3390/nu13113688
  • Peer Reviewed
• [Journal Article] Sarcopenia-derived exosomal micro-RNA 16-5p disturbs cardio-repair via a pro-apoptotic mechanism in myocardial infarction in mice (2021)
  • Author(s): Hayasaka Taiki、Takehara Naofumi、Aonuma Tatsuya、Kano Kohei、Horiuchi Kiwamu、Nakagawa Naoki、Tanaka Hiroki、Kawabe Jun-ichi、Hasebe Naoyuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 19163-19163
  • DOI: 10.1038/s41598-021-98761-8
  • Peer Reviewed / Open Access
• [Journal Article] Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis (2021)
  • Author(s): Ho Jean K.、Moriarty Frank、Manly Jennifer J.、Larson Eric B.、Evans Denis A.、Rajan Kumar B.、Hudak Elizabeth M.、Hassan Lamiaa、Liu Enwu、Sato Nobuyuki、Hasebe Naoyuki、Laurin Danielle、Carmichael Pierre-Hugues、Nation Daniel A.
  • Journal Title: Hypertension Volume: 78 Issue: 3 Pages: 629-643
  • DOI: 10.1161/hypertensionaha.121.17049
  • Peer Reviewed
• [Journal Article] Back somersault-induced atrioventricular nodal reentrant tachycardia ? A case of a 15-year-old promising gymnast (2021)
  • Author(s): Hayasaka Taiki、Kawamura Yuichiro、Kobayashi Yuya、Kitani Yuya、Hontani Misako、Sugiyama Eitaro、Sumitomo Kazuhiro、Tanabe Yasuko、Akasaka Kazumi、Takeuchi Toshiharu、Sato Nobuyuki、Hirasawa Kunihiko、Hasebe Naoyuki
  • Journal Title: Journal of Cardiology Cases Volume: 24 Issue: 1 Pages: 14-19
  • DOI: 10.1016/j.jccase.2020.12.004
  • Peer Reviewed
• [Journal Article] Pericyte-specific deletion of Ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature (2021)
  • Author(s): Kiwamu Horiuchi, Kohei Kano, Akiho Minoshima, Taiki Hayasaka, Atsushi Yamauchi, Takamitsu Tatsukawa, Risa Matsuo, Yuri Yoshida, Yui Tomita, Maki Kabara, Naoki Nakagawa, Naofumi Takehara, Naoyuki Hasebe, and Jun-ichi Kawabe
  • Journal Title: American Journal of Physiology Heart and Circulatory Physiology Volume: - Issue: 6 Pages: H2438-H2447
  • DOI: 10.1152/ajpheart.00931.2020
  • Peer Reviewed / Open Access / Int'l Joint Research