心血管低酸素研究グループの研究内容

現在、私達は特に2種類のシグナル経路、1)細胞の低酸素応答を転写レベルで司る低酸素誘導型転写因子Hypoxia inducible factor(HIF)と、2)血管内皮細胞増殖因子Vascular Endothelial Growth Factor(VEGF)に特に注目して解析を行っています。HIF, VEGF関連遺伝子の組織特異的欠損マウスを用いた個体レベルでの疾患モデルでの解析と併せて、イメージングプローブを用いた低酸素領域の可視化、細胞およびマウスの低酸素飼育および細胞代謝フラックス解析などの手法を用いて研究を続けています。

現在行なっている具体的な研究テーマ

1)低酸素応答と心臓リモデリング
2)転写因子HIFとクロマチン制御機構
3)肺高血圧、右心不全における低酸素シグナルの役割
4)心血管病態におけるVEGFシグナル

低酸素1

主要論文

Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, Miyazawa H, Yamaguchi Y, Miura M, Jenkins DM, Choi H, Kim JW, Asagiri M, Cowburn AS, Abe H, Soma K, Koyama K, Katoh M, Sayama K, Goda N, Johnson RS, Manabe I, Nagai R and Komuro I. HIF-1α-PDK1 axis induced active glycolysis plays an essential role in macrophage migratory capacity.
Nature Communications. 2016: 7, Article Number 11635

Takeda N, Maemura K. Circadian clock and the onset of cardiovascular events. Hypertens Res. 2016 Feb 18. doi: 10.1038/hr.2016.9.

Mori Y, Takahashi N, Polat OK, Kurokawa T, Takeda N, Inoue M. Redox-sensitive transient receptor potential channels in oxygen sensing and adaptation. Pflugers Arch. 2016;468(1):85-97.

Tojo Y, Sekine H, Hirano I, Pan X, Souma T, Tsujita T, Kawaguchi SI, Takeda N, Takeda K, Fong GH, Dan T, Ichinose M, Miyata T, Yamamoto M, Suzuki N. Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes.
Mol Cell Biol. 2015;35(15):2658-72.

Takeda N, Maemura K. The role of clock genes and circadian rhythm in the development of cardiovascular diseases.
Cell Mol Life Sci. 2015;72(17):3225-34.

Abe H, Iguchi N, Utanohara Y, Inoue K, Takamisawa I, Seki A, Tanizaki K, Takeda N, Tohbaru T, Asano R, Nagayama M, Takayama M, Umemura J, Sumiyoshi T, Tomoike H. Noninvasive diagnosis of coronary artery disease by 123I-BMIPP/201TlCl dual myocardial SPECT in patients with heart failure.
International Journal of Cardiology 2014: S0167-5273(14)01676-3.

Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S, Toriguchi K, Tanabe K, Seo S, Taura K, Machida K, Takeda N, Uemoto S, Asagiri M. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-caused acute liver failure.
FEBS Open Bio 2014;4:777-87.

Ruthenborg RJ, Ban JJ, Kim JW, Wazir A, Takeda N, Kim JW. Regulation of Wound Healing and Fibrosis by Hypoxia and Hypoxia-Inducible Factor-1.
Mol Cells. 2014;37(9):637-43.

Yamagata K, Goto Y, Nishimasu H, Morimoto J, Ishitani R, Dohmae N, Takeda N, Nagai R, Komuro I, Suga H, Nureki O. Structural Basis for Potent Inhibition of SIRT2 Deacetylase by a Macrocyclic Peptide Inducing Dynamic Structural Change.
Structure. 2014;4;22(2):345-52.

Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER, Johnson RS. HIF isoforms in the skin differentially regulate systemic arterial pressure.
Proc Natl Acad Sci U S A. 2013:110(43):17570-5.

Saito T, Takeda N, Amiya E, Nakao T, Abe H, Semba H, Soma K, Koyama K, Hosoya Y, Imai Y, Isagawa T, Watanabe M, Manabe I, Komuro I, Nagai R, Maemura K. VEGF-A Induces its Negative Regulator, Soluble Form of VEGFR-1, by Modulating its Alternative Splicing.
FEBS Lett. 2013;587(14):2179-85.

Semba H, Sawada H, Uejima T, Takeda N, Soma K, Abe H, Yamashita T and Nagai R. Basic Echocardiographic Features of Patients with Latent Left Ventricular Outflow Tract Obstruction without Left Ventricular Hypertrophy.
Int Heart J. 2012;53(4):230-3.

Abe H, Takeda N, Aoki H, Nagai R. Sinus of valsalva aneurysm accompanying bicuspid aortic valve. Intern Med. 2012;51(10):1275.

Abe H, Takayama M, Takeda N, Takanashi S, Nagai R. Successful surgical repair of a giant coronary-pulmonary artery fistula: role of magnetic resonance imaging.
Eur Heart J Cardiovasc Imaging. 2012 May 15.

Kim JW, Evans C, Weidemann A, Takeda N, Lee YS, Stockmann C, Branco-Price C, Brandberg F, Leone G, Ostrowski MC, Johnson RS. Loss of fibroblast HIF-1α accelerates tumorigenesis. 
Cancer Res. 2012; 72(13):3187-95.

Soma K, Abe H, Takeda N, Shintani Y, Takazawa Y, Kojima T, Fujiu K, Semba H, Yamashita H, Hirata Y, Fukayama M, Nagai R.  Myocardial involvement in patients with osteogenesis imperfecta. Int Heart J. 2012;53(1):75-7.

Takeda N, Maemura K. Circadian clock and cardiovascular disease. J Cardiol. 2011 May;57(3):249-56.

Stockmann C, Kirmse S, Helfrich I, Weidemann A, Takeda N, Doedens A, Johnson RS. A wound size-dependent effect of myeloid cell-derived vascular endothelial growth factor on wound healing. J Invest Dermatol. 2011 Mar;131(3):797-801.

Takeda N, O'Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010 Mar 1;24(5):491-501.

Takeda N, Memura K. Cardiovascular disease, chronopharmacotherapy, and the molecular clock. Adv Drug Deliv Rev. 2010 Jul 31;62(9-10):956-66.

Takeda N, Maemura K. Circadian clock and vascular disease. Hypertens Res. 2010 Jul;33(7):645-51.

Weidemann A, Krohne TU, Aguilar E, Kurihara T, Takeda N, Dorrell MI, Simon MC, Haase VH, Friedlander M, Johnson RS. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia. 2010 Aug;58(10):1177-85.

Stockmann C, Kerdiles Y, Nomaksteinsky M, Weidemann A, Takeda N, Doedens A, Torres-Collado AX, Iruela-Arispe L, Nizet V, Johnson RS. Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4329-34.

Weidemann A, Kerdiles YM, Knaup KX, Rafie CA, Boutin AT, Stockmann C, Takeda N, Scadeng M, Shih AY, Haase VH, Simon MC, Kleinfeld D, Johnson RS. Glial response is an essential component of hypoxia-induced erythropoiesis. J Clin Invest. 2009 Nov;119(11):3373-83.

Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008 Dec 11;456 (7223):814-8.

Takeda N, Maemura K, Horie S, Oishi K, Imai Y, Harada T, Saito T, Shiga T, Amiya E, Manabe I, Ishida N, Nagai R. Thrombomodulin is a clock-controlled gene in vascular endothelial cells. J Biol Chem. 2007 Nov 9; 282(45):32561-7

Takeda N, Maemura K. Chronobiology of acute myocardial infarction. Molecular Biology. Biological Rhythms Research. 2007; 38(3): 233-245.

Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T, Manabe I, Nagai R. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ Res. 2004 Jul 23; 95(2): 146-53.

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