Kyushu University Academic Staff Educational and Research Activities Database
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Tetsuro Ago Last modified date:2021.10.27

Associate Professor / Department of Medicine and Clinical Science, Graduate School of Medical Sciences
Department of Clinical Medicine
Faculty of Medical Sciences


Undergraduate School
Administration Post
Other


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Homepage
https://kyushu-u.pure.elsevier.com/en/persons/tetsuro-ago
 Reseacher Profiling Tool Kyushu University Pure
http://www.med.kyushu-u.ac.jp/intmed2/
Department of Clinical Medicine, Graduate School of Medical Sciences, Kyushu University .
http://www.stroke.med.kyushu-u.ac.jp/
脳循環研究室が推進する福岡脳卒中データベース研究(Fukuoka Stroke Registry: FSR) のホームページ .
Academic Degree
MD, PhD
Country of degree conferring institution (Overseas)
Yes
Field of Specialization
Internal medicine, Strokology, Molecular & Cellular Biology
ORCID(Open Researcher and Contributor ID)
https://orcid.org/0000-0003-4560-6594
Total Priod of education and research career in the foreign country
03years00months
Research
Research Interests
  • Molecular mechanisms of repair and regeneration in brain after cerebrovascular diseases
    keyword : brain infarction, neuronal repair/regeneration, endothelial cells, pericytes
    2008.04.
  • Roles of Redox (oxidative stress) in regulating cardiovascular diseases
    keyword : redox, NADPH oxidase, antioxidants, atherosclerosis
    2001.04.
  • Multicenter hospital-based prospective study of acute stroke (Acute stroke cohort study; Fukuoka stroke Registry).
    keyword : stroke database, multi-centered trial
    2008.04.
  • Exploration of genetic factors and biomarkers of cerebrovascular diseases
    keyword : brain infarction, biomarker, genes, proteins
    2008.04.
  • Elucidation of activation mechanisms of phagocyte NADPH oxidase
    keyword : Phagocyte NADPH oxidase
    1996.04~2002.03.
Academic Activities
Reports
1. Kamouchi M, Ago T, Kuroda J, Kitazono T. , The possible roles of brain pericytes in brain ischemia and stroke, Cell Mol Neurobiol, 2012.03.
2. Ago T, Kuroda J, Kamouchi M, Sadoshima J, Kitazono T. , Pathophysiological Roles of NADPH Oxidase/Nox Family Proteins in the Vascular System – Review and Perspective – , Circulation Journal , 2011.07, [URL].
3. Kamouchi M, Ago T, Kitazono T., Brain pericytes: emerging concepts and functional roles in brain homeostasis., Cell Mol Neurobiol. , 2011.03.
4. Ago T, Matsushima S, Kuroda J, Zablocki D, Kitazono T, Sadoshima J., The NADPH oxidase Nox4 and aging in the heart, Aging, 2010.12.
5. Ago T, Sadoshima J. , Thioredoxin1 as a negative regulator of cardiac hypertrophy. , 2007.06.
Papers
1. Kiyohara T, Matsuo R, Hata J, Nakamura K, Wakisaka Y, Kamouchi M, Kitazono T, Ago T, beta-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke, STROKE, 10.1161/STROKEAHA.120.031392, 52, 8, 2621-2628, 2021.08.
2. Shibahara T, Ago T, et al., Pericyte-Mediated Tissue Repair through PDGFRbeta Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke, eNeuro, 10.1523/ENEURO.0474-19.2020, 2020.03.
3. Kuniyuki Nakamura, Tomoko Ikeuchi, Kazuki Nara, Craig S. Rhodes, Peipei Zhang, Yuta Chiba, Saiko Kazuno, Yoshiki Miura, Tetsuro Ago, Eri Arikawa-Hirasawa, Yoh Suke Mukouyama, Yoshihiko Yamada, Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier, The Journal of cell biology, 10.1083/jcb.201807178, 218, 10, 3506-3525, 2019.10, Ischemic stroke causes blood-brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2-/--TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2-/--TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke..
4. Yoji Yoshikawa, Tetsuro Ago, Junya Kuroda, Yoshinobu Wakisaka, Masaki Tachibana, Motohiro Komori, Tomoya Shibahara, Hideyuki Nakashima, Kinichi Nakashima, Takanari Kitazono, Nox4 Promotes Neural Stem/Precursor Cell Proliferation and Neurogenesis in the Hippocampus and Restores Memory Function Following Trimethyltin-Induced Injury, Neuroscience, 10.1016/j.neuroscience.2018.11.046, 398, 193-205, 2019.02, Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H 2 O 2 , the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4 / mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4 / mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4 / animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4 / mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function..
5. Motohiro Komori, Tetsuro Ago, Yoshinobu Wakisaka, Kuniyuki Nakamura, Masaki Tachibana, Yoji Yoshikawa, Tomoya Shibahara, Kei Yamanaka, Junya Kuroda, Takanari Kitazono, Early initiation of a factor Xa inhibitor can attenuate tissue repair and neurorestoration after middle cerebral artery occlusion, Brain Research, 10.1016/j.brainres.2019.05.020, 1718, 201-211, 2019.09, The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO)in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood–brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized..
6. Why are pericytes important for brain functions?.
7. Ago T, Matsuo R, Hata J, Wakisaka Y, Kuroda J, Kitazono T, Kamouchi M. Insulin resistance and clinical outcomes after ischemic stroke., Insulin resistance and clinical outcomes after ischemic stroke., Neurology, 90, 17, 1470-1477, 2018.05, インスリン抵抗性と脳梗塞発症後機能転帰の関連について検討した.本検討では4,655名の急性期脳梗塞患者(平均年齢70.3歳,男性63,5%,入院前自立,発症7日以内,入院前-中にインスリン治療を受けていない患者)について解析している.
入院後,空腹時血糖およびインスリン値によって計算されたHOMA-IRをインスリン抵抗性の指標として用いた.入院後の神経増悪の有無,3ヶ月後の転帰不良(mRS 3以上),及び 3ヶ月後再発・死亡との関連について解析した.
HOMA-IRを値の低い方から5群(Q1-Q5)にわけ,Q1を基準とすると,Q5では入院中の神経症候改善率が低く(オッズ比 0.68 [95% confidence interval, 0.56–0.83],転帰不良となるオッズ比が高値であった(2.02 [1.52–2.68]).
3ヶ月後の再発や死亡との関連は認められなかった.非糖尿病・非肥満の患者群でもこの関連は維持された.年齢,性,脳梗塞病型・重症度別に層別解析を行ったが異質性は認められなかった..
8. Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne Katrin Giese, Sander W. Van Der Laan, Solveig Gretarsdottir, Christopher D. Anderson, Michael Chong, Hieab H.H. Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M. Bartz, Oscar R. Benavente, Steve Bevan, Giorgio B. Boncoraglio, Robert D. Brown, Adam S. Butterworth, Caty Carrera, Cara L. Carty, Daniel I. Chasman, Wei Min Chen, John W. Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul I.W. De Bakker, Anita L. Destefano, Marcel Den Hoed, Qing Duan, Stefan T. Engelter, Guido J. Falcone, Rebecca F. Gottesman, Raji P. Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B. Harris, Ahamad Hassan, Aki S. Havulinna, Susan R. Heckbert, Elizabeth G. Holliday, George Howard, Fang Chi Hsu, Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes, Nature genetics, 10.1038/s41588-018-0058-3, 50, 4, 524-537, 2018.04, Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy..
9. Tachibana M, Ago T, Wakisaka Y, Kuroda J, Kitazono T, Early reperfusion after brain ischemia has beneficial effects beyond rescuing neurons, Stroke, 2017.08.
10. Nishimura A, Ago T, Kuroda J, et al., Detrimental role of pericyte Nox4 in the acute phase of brain ischemia., J Cereb Blood Flow Metab, 36, 6, 1143-1154, 2016.06.
11. Nakamura K, Arimura K, Ago T, et al., Possible involvement of basic FGF in the upregulation of PDGFR beta in pericytes after ischemic stroke, BRAIN RESEARCH, 10.1016/j.brainres.2015.11.003, 1630, 98-108, 2016.01.
12. Makihara N, Ago T, et al., Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke, Exp Neurol, 2015.02.
13. Ishitsuka K, Ago T(Corresponding author), Arimura K, Nakamura K, Tokami H, Makihara N, Kuroda J, Kamouchi M, Kitazono T., Neurotrophin production in brain pericytes during hypoxia: a role of pericytes for neuroprotection, Microvascular Research, 83, 3, 352-9, 2012.05.
14. Arimura K, Ago T(Corresponding author), Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J, Sugimori H, Ooboshi H, Sasaki T, Kitazono T., PDGF receptor β signaling in pericytes following ischemic brain injury, Current Neurovascular Research, 9, 1, 1-9, 2012.02.
15. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J, NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart., PNAS, 107, 35, 15565-70, 2010.08.
16. Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J., Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes., Circulation Research, 2010.04.
17. Ago T, Kitazono T, Kuroda J, Kumai Y, Kamouchi M, Ooboshi H, Wakisaka M, Kawahara T, Rokutan K, Ibayashi S, Iida M, NAD(P)H oxidases in rat basilar arterial endothelial cells, Stroke, 10.1161/01.STR.0000163111.05825.0b, 36, 5, 1040-1046, 36(5): 1040-1046 , 2005.05.
18. Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, Iida M. , Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase., Circulation, 10.1161/01.CIR.0000105680.92873.70, 109, 2, 227-233, 109(2): 227-233., 2004.01.
19. Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, Sumimoto H. , Phosphorylation of p47phox directs PX domain from SH3 domain towards phosphoinositides, leading to phagocyte NADPH oxidase activation. , PNAS, 10.1073/pnas.0735712100, 100, 8, 4474-4479, 100(8): 4474-9., 2003.04.
20. Hiroaki H, Ago T, Ito T, Sumimoto H, Kohda D. , Solution structure of the PX domain, a target of the SH3 domain. , Nature Structural Biology, 10.1038/88591, 8, 6, 526-530, 8, 526-30 , 2001.08.
21. Ago T, Nunoi H, Ito T, Sumimoto H., Mechanism for phosphorylation-induced activation of the phagocyte NADPH oxidase protein p47phox. Triple replacement of serines 303, 304, and 328 with aspartates disrupts the SH3 domain-mediated intramolecular interaction in p47phox, thereby activating the oxidase. , J Biol Chem , 10.1074/jbc.274.47.33644, 274, 47, 33644-33653, 274(47): 33644-33653., 1999.11.
Presentations
1. Ago T, Reciprocal interaction between pericytes and macrophage in post-stroke tissue repair and functional recovery. “High Impact Articles in Post-stroke Outcomes 2020, International Stroke Conference 2021, 2021.03.
2. Gordon Research Conference on Nox family NADPH oxidases 2010, [URL].
3. , [URL].
Membership in Academic Society
  • Cardiovascular Stroke Society of Japan