2007 Fiscal Year Final Research Report Summary
Pthophysiological significance of target genes of NRSF, a new transcriptional suppressor, in congestive heart failure
| Project/Area Number |
18390238
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Nara Medical University |
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Principal Investigator |
SAITO Yoshihiko Nara Medical University, First Department of Internal Medicine, Professor (30250260)
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| Co-Investigator(Kenkyū-buntansha) |
UEMURA Shiro Nara Medical University, First Department of Internal Medicine, Assistant Professor (80232792)
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| Project Period (FY) |
2006 – 2007
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| Keywords | heart failure / NRSF / NRSE system / ANP / Aldosterone / CYP11B2 / CACNA1H / Cav 3.2 / H295R cells |
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| Research Abstract |
Aldosterone, one of key molecules which are involved in pathogenesis in heart failure, is synthesized by a specific synthase, CYP11B2, and its gene expression is regulated Ca influx into via T-type calcium channel, Cav 3.2, in adrenal cortical cells. However, the molecular mechanism for aldosterone synthesis in heart failure is not fully understood.
Recently we reported that Neuron restrictive silencer factor (NRSF), which binds to neuron restrictive silencer element (NRSE) to suppress transcription of NRSE-containing genes, is involved in the re-induction of a number of cardiac embryonic genes in vitro and in vivo. Mice over-expressing dominant negative NRSF show dilated cardiomyopathy-like cardiac phenotypic changes and sudden cardiac death due to fatal ventricular arrhythmia.
We also identified the sequence highly homologous to NRSE sequence is located in transcriptional regulatory region of the CYP11B2 gene and CACNA1H gene, the latter of which encodes subunit of Cav3.2.
Here we examined the roles of the NRSE/NRSF system in aldosterone synthesis in human adrenocortical (H295R) cells. Inhibiting endogenous NRSF function by adenovirus vector containing dominant-negative NRSF (AD/dnNRSF) markedly increased aldosterone secretion and CYP11B2 mRNA. AD/dnNRSF also increased levels of CACNA1H mRNA. Efonidipine, dual T/L-type calcium channel blocker, inhibited dnNRSF-induced CYP11B2 mRNA expression and CYP11B2 reporter gene activity from constructs containing a mutated or missing NRSE sequence. Moreover, AD/dnNRSF attenuated AngII- and K^+-induced increases in CYP11B2 mRNA levels.
The present findings suggest the NRSE/NRSF system controls aldosterone synthesis in the adrenal gland, which is one of extracardiac compensatory mechanism in heart failure.
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Research Products
(59 results)
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[Journal Article] Effects of a 3-Hydroxy-3-Methylglutaryl coenzyme a reductase inhibitor, fluvastatin, on coronary spasm after withdrawal of calcium-channel blockers2008
Author(s)
H. Yasue, Y. Mizuno, E. Harada, T. Itoh, H. Nakagawa, M. Nakayama, H. Ogawa, S. Tayama, T. Honda, S. Hokimoto, S. Ohshima, Y. Hokamura, K. Kugiyama, M. Horie, M. Yoshimura, M. Harada, S. Uemura, Y. Saito
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Journal Title
J Am Coll Cardiol 51
Pages: 1742-1748
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Establishment of embryonic stem cells secreting human factorVll[ for cell-based treatment of hemophilia A2008
Author(s)
S. Kasuda, A. Kubo, Y. Sakurai, S. Irion, K. Ohashi, K. Tatsumi, Y. Nakajima, Y. Saito, K. Hatake, P. Steven, M. Shima, A. Yoshioka
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Journal Title
J Thromb Haemost (in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Acute Myocardial Infarction as a Systemic Prothrombotic Condition Evidenced by Increased von Willebrand Factor Protein Over ADAMTS13 Activity in Coronary and Systemic Circulation2008
Author(s)
M. Horii, S. Uemura, M. Uemura, M. Matsumoto, H. Ishizashi, K. Imagawa, H. Iwama, Y. Takeda, H. Kawata, T. Nakajima, Y. Fujimura, Y. Saito
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Journal Title
Heart and Vessel (in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Specific Mineralocorticoid Receptor Blocker Eplerenone Attenuates Left Ventricular Remodeling in Mice Lacking the Gene Encoding Guanylyl Cyclase-A2008
Author(s)
Q, Zhang, Y. Saito, N. Naya, K. Imagawa, S. Somekawa, H. Kawata, Y. Takeda, S. Uemura, I. Kishimoto, K. Nakao
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Description
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[Journal Article] Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial to mesenchymal transition2007
Author(s)
D F. Higgins, K. Kimura, W M. Bernhardt, N. Shrimanker, Y. Akai, B. Hohenstein, Y. Saito, R S, Johnson, M. Kretzler, C D. Cohen, K.-U. Eckardt, M. Iwano, V H. Haase
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Journal Title
J Clin Invest 117
Pages: 3810-3820
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Elevated Levels of Fractalkine Expression and Accumulation of CD16+ Monocytes in Glomeruli of Active Lupus Nephritis2007
Author(s)
S. Yoshimoto, K. Nakatani, M. Iwano, O. Asai, K. Samejima, H. Sakan, M. Terada, K. Harada, Y. Akai, H. Shiiki, M. Nose, Y. Saito
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Journal Title
American Journal of Kidney Diseases 50
Pages: 47-58
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Ultrasound accelerates thrombolysis of acutely induced platelet-rich thrombi similar to those in acute myocardial infarction2007
Author(s)
H. Kawata, N. Naya, Y. Takemoto, S. Uemura, T. Nakajima, M. Horii, Y. Takeda, S. Fujimoto, A. Yamashita, Y. Asada, Y. Saito
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Journal Title
Circ J 71
Pages: 1643-1648
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic disruption of angiotensin II type la receptor improves long-term survival of mice with chronic severe aortic regurgitation2007
Author(s)
M. Nakanishi, M. Harada, I. Kishimoto, K. Kuwahara, R. Kawakami, Y. Nakagawa, S. Yasuno, S. Usami, H. Kinoshita, Y. Adachi, A. Fukamizu, Y. Saito, K. Nakao
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Journal Title
Circ J 71
Pages: 1310-1316
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction2007
Author(s)
T. Tatsumi, E. Ashihara, T. Yasui, S. Matsunaga, A. Kido, Y. Sasada, S. Nishikawa. M. Hadase, M. Koide, R. Nakamura, H. Irie, K. Ito, A. Matsui, H. Matsui, M. Katamura, S. Kusuoka, S. Matoba, S. Okayama, M. Horii, S. Uemura, C. Shimazaki, H. Tsuji, Y. Saito, H. Matsubara
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Journal Title
Circ J 71
Pages: 1199-1207
Description
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[Journal Article] A Genetic Locus Controlling Aging-sensitive Regression of B Lymphopoiesis in an Autoimmune-prone MRL/lpr Strain of Mice2007
Author(s)
K. Nakatani, Qu, WM, Zhang, MC, H. Fujii, H. Furukawa, T. Miyazaki, M. Iwano, Y. Saito, M. Nose, M. Ono
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Journal Title
Scand J Immunol 66
Pages: 654-61
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The endothelial nitric oxide synthase gene -786T/C polymorphism is a predictive factor for reattacks of coronary spasm2007
Author(s)
T. Nishijima, M. Nakayama, M. Yoshimura, K. Abe, M. Yamamuro, S. Suzuki, M. Shono, S. Sugiyama, Y. Saito, Y. Miyamoto, K. Nakao, H. Yasue, H. Ogawa
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Journal Title
Pharmacogenet Genomics 17
Pages: 581-587
Description
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[Journal Article] Inflammatory response to acute myocardial infarction augments neointimal hyperplasia after vascular injury in a remote artery2006
Author(s)
M. Takaoka, S. Uemura, H. Kawata, K. Imagawa, Y. Takeda, K. Nakatani, N. Naya, M. Horii, S. Yamano, Y. Miyamoto, Y. Yoshimasa, Y. Saito
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Journal Title
Arterioscler Thromb Vasc Biol 26
Pages: 2083-2089
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cardiac expression of placental growth factor predicts the improvement of chronic phase left ventricular function in patients with acute myocardial infarction2006
Author(s)
H. Iwama, N. Naya, K. Imagawa, Y. Takemoto, O. Asai, K. Onoue, S. Okayama, S. Somekawa, Y. Kida, Y. Takeda, M. Takaoka, H. Kawata, M. Horii, T. Nakajima, N. Doi, Y. Saito
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Journal Title
J Am Coll Cardiol 47
Pages: 1559-1567
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Usefulness of 16-slice multislice spiral computed tomography for follow-up study of coronary stent implantation2006
Author(s)
M. Watanabe, S. Uemura, H. Iwama, S. Okayama, Y. Takeda, H. Kawata, M. Horii, T. Nakajima, S. Hirohashi, K. Kichikawa, A. Ookura, Y. Saito
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Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes2006
Author(s)
Y. Nakagawa, K. Kuwahara, M. Harada, N. Takahashi, S. Yasuno, Y. Adachi, R. Kawakami, M. Nakanishi, K. Tanimoto, S. Usami, H. Kinoshita, Y. Saito K. Nakao
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Journal Title
J Mol Cell Cardiol 41
Pages: 1010-1022
Description
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