Elucidation of molecular mechanisms regulating the gene expression of fetal cardiac ion channels and its implication as a novel therapeutic target for the treatment of heart failure

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390224
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto University
• Principal Investigator: KUWAHARA Koichiro Kyoto University, 医学研究科, 講師 (30402887)
• Co-Investigator(Kenkyū-buntansha): MURAKAMI Masao 京都大学, 医学研究科, 助教 (10302605)
• Co-Investigator(Renkei-kenkyūsha): TAKANO Makoto 自治医科大学, 医学部, 教授 (30236252) ; ARAI Yuji 国立循環器病研究センター研究所, 分子生物学部, 室長 (30202724)
• Project Period (FY): 2008 – 2010
• Keywords: イオンチャル / 心不全 / 転写調節 / 不整脈

Research Abstract

Genetic remodeling contributes to the progression of pathological cardiac remodeling and heart failure by affecting myocardial cellular function and survival. In this study we evaluated the transcriptional regulation of fetal cardiac ion channels gene expression and the significance of these fetal ion channels as novel therapeutic targets for the treatment and prevention of heart failure. Our studies have revealed the transcriptional network regulating the expression of cardiac fetal-type ion channels, which are involved in the development of cardiac dysfunction and arrhythmias and potential therapeutic targets for the treatment and prevention of heart failure.

Research Products

• [Journal Article] Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-a. (2011)
  • Author(s): Fujiwara M, Yan P, Otsuji TG, Narazaki G, Uosaki H, Fukushima H, Kuwahara K, Harada M, Matsuda H, Matsuoka S, Okita K, Takahashi K, Nakagawa M, Ikeda T, Sakata R, Mummery CL, Nakatsuji N, Yamanaka S, Nakao K, Yamashita JK.
  • Journal Title: PLoS One. 6(2) Pages: 16734
  • Peer Reviewed
• [Journal Article] Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides. (2011)
  • Author(s): Nishikimi T, Kuwahara K, Nakao K.
  • Journal Title: J Cardiol. ([Epub ahead of print]in press)
  • Peer Reviewed
• [Journal Article] Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes. (2011)
  • Author(s): Hata L, Murakami M, Kuwahara K, Nakagawa Y, Kinoshita H, Usami S, Yasuno S, Fujiwara M, Kuwabara Y, Minami T, Yamada Y, Yamada Y, Nakao K, Ueshima K, Nishikimi T, Nakao K.
  • Journal Title: J Mol Cell Cardiol. (in press)
  • Peer Reviewed
• [Journal Article] Pathophysiological Remodeling of Mouse Cardiac Myocytes Expressing Dominant Negative Mutant of Neuron Restrictive Silencing Factor. (2010)
  • Author(s): Takano M, Kinoshita H, Shioya T, Itoh M, Nakao K, Kuwahara K.
  • Journal Title: Circ J. (in press)
  • Peer Reviewed
• [Journal Article] MRTF-A is a common mediator of mechanical stress-and neurohumoral stimulation-induced cardiac hypertrophic signaling leading to activation of BNP gene expression. (2010)
  • Author(s): Kuwahara K, Kinoshita H, Kuwabara Y, Nakagawa Y, Usami S, Minami T, Yamada Y, Fujiwara M, Nakao K.
  • Journal Title: Mol Cell Biol. 30(17) Pages: 4134-4148
  • Peer Reviewed
• [Journal Article] Regulation and significance of atrial and brain natriuretic peptides as cardiac hormones. (2010)
  • Author(s): Kuwahara K, Nakao K.
  • Journal Title: Endocr J. 57(7) Pages: 555-565
  • Peer Reviewed
• [Journal Article] Myocardin-Related Transcription Factor-A Controls Myofibroblast Activation and Fibrosis in Response to Myocardial Infarction. (2010)
  • Author(s): Small EM, Thatcher JE, Sutherland LB, Kinoshita H, Gerard RD, Richardson JA, Dimaio JM, Sadek H, Kuwahara K, Olson EN.
  • Journal Title: Circ Res. 107(2) Pages: 294-304
  • Peer Reviewed
• [Journal Article] Inhibition of TRPC6 Channel Activity Contributes to the Anti-hypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart. (2010)
  • Author(s): Kinoshita H, Kuwahara K, Nishida M, Jiang Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Li Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K, Nakao K.
  • Journal Title: Circ Res. 106(12) Pages: 1849-1860
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice. (2010)
  • Author(s): Rong X, Li Y, Ebihara K, Zhao M, Naowaboot J, Kusakabe T, Kuwahara K, Murray M, Nakao K.
  • Journal Title: Diabetologia. (in press)
  • Peer Reviewed
• [Journal Article] Podocyte-specific expression of tamoxifen-inducible Cre recombinase in mice. (2010)
  • Author(s): Yokoi H, Kasahara M, Mukoyama M, Mori K, Kuwahara K, Fujikura J, Arai Y, Saito Y, Ogawa Y, Kuwabara T, Sugawara A, Nakao K.
  • Journal Title: Nephrol Dial Transplant. 25(7) Pages: 2150-2154
  • Peer Reviewed
• [Journal Article] Vasodilator therapy with hydralazine induces angiotensin AT receptor-mediated cardiomyocyte growth in mice lacking guanylyl cyclase-A. (2010)
  • Author(s): Li Y, Saito Y, Kuwahara K, Rong X, Kishimoto I, Harada M, Horiuchi M, Murray M, Nakao K.
  • Journal Title: Br J Pharmacol. 159(5) Pages: 1133-1142
  • Peer Reviewed
• [Journal Article] p300 plays a critical role inmaintaining cardiac mitochondrial function and cell survival in postnatal hearts. (2009)
  • Author(s): Nakagawa Y, Kuwahara K, Takemura G, Akao M, Kato M, Arai Y, Takano M, Harada M, Murakami M, Nakanishi M, Usami S, Yasuno S, Kinoshita H, Fujiwara M, Ueshima K, Nakao K.
  • Journal Title: Circ.Res. 105(8) Pages: 746-754
  • Peer Reviewed
• [Journal Article] T-type Ca^<2+> channel blockade prevents sudden death in mice with heart failure. (2009)
  • Author(s): Kinoshita H, Kuwahara K, Takano M, Arai Y, Kuwabara Y, Yasuno S, Nakagawa Y, Nakanishi M, Harada M, Fujiwara M, Murakami M, Ueshima K, Nakao K.
  • Journal Title: Circulation. 120(9) Pages: 743-752
  • Peer Reviewed
• [Journal Article] The cardiac pacemaker-specific channel Hcn4 is a direct transcriptional target of MEF2. (2009)
  • Author(s): Kuratomi S, Ohmori Y, Ito M, Shimazaki K, Muramatsu SI, Mizukami H, Uosaki H, Yamashita J, Arai Y, Kuwahara K, Takano M.
  • Journal Title: Cardiovasc Res. 83(4) Pages: 682-687
  • Peer Reviewed
• [Journal Article] Endogenous cardiac natriuretic peptides protect the heart in a mouse model of dilated cardiomyopathy and sudden death. (2009)
  • Author(s): Yasuno S, Usami S, Kuwahara K, Nakanishi M, Arai Y, Kinoshita H, Nakagawa Y, Fujiwara M, Murakami M, Ueshima K, Harada M, Nakao K.
  • Journal Title: Am J Physiol Heart Circ Physiol. 296(6) Pages: 1804-1810
  • Peer Reviewed
• [Journal Article] Natriuretic peptide receptor/guanylyl cyclase-A inhibits angiotensin II type 2 receptor-mediated pro-hypertrophic signaling in the heart. (2009)
  • Author(s): Li Y, Saito Y, Kuwahara K, Rong X, Kishimoto I, Harada H, Adachi Y, Nakanishi M, Kinoshita H, Horiuchi M, Murray M, Nakao K.
  • Journal Title: Endocrinology. 150(8) Pages: 3759-3765
  • Peer Reviewed
• [Journal Article] Fgf16 is required for cardiomyocyte proliferation in the mouse embryonic heart. (2008)
  • Author(s): Hotta Y, Sasaki S, Konishi M, Kinoshita H, Kuwahara K, Nakao K, Itoh N.
  • Journal Title: Dev Dyn. 24;237(10) Pages: 2947-2954
  • Peer Reviewed
• [Journal Article] Association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase (GC)-A gene with essential hypertension in the Japanese. (2008)
  • Author(s): Usami S, Kishimoto I, Saito Y, Harada M, Kuwahara K, Nakagawa Y, Nakanishi M, Yasuno S, Kangawa K, Nakao K.
  • Journal Title: Hypertens Res. 31(1) Pages: 89-96
  • Peer Reviewed
• [Presentation] T-type Ca2+ Channel Blockade Improved Cardiac Autonomic Nervous System Imbalance and Reduced Sudden Death in Mice Model of Chronic Heart Failure. (2010)
  • Author(s): Kinoshita H, Kuwahara K, et al.
  • Organizer: European Society of Cardiology Congress
  • Place of Presentation: Stockholm, Sweden.
  • Year and Date: 20100828-20100901
• [Presentation] Blockade of TRPC Channel Prevents Pathological Cardiac Hypertrophy. (2010)
  • Author(s): Kinoshita H, Kuwahara K, et al.
  • Organizer: Basic_Cardiovascular Sciences 2010 Scientific Sessions
  • Place of Presentation: Rancho Mirage, CA, USA
  • Year and Date: 20100719-20100722
• [Presentation] Inhibition of TRPC6 Channel Contributes to the Anti-hypertrophic Effects Exerted by Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart. (2010)
  • Author(s): Kuwahara K, et al.
  • Organizer: 20th European Meeting of Hypertension
  • Place of Presentation: Oslo, Norway
  • Year and Date: 20100618-20100621
• [Presentation] NRSF maintains normal cardiac structure and function. (2010)
  • Author(s): Kuwahara K, et al.
  • Organizer: 20th World Congress of the International Society of Heart Research
  • Place of Presentation: Kyoto.
  • Year and Date: 20100513-20100516
• [Presentation] Inhibition of TRPC6 Channel Conributes to the Anti-hypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart. (2010)
  • Author(s): Kuwahara K, et al.
  • Organizer: 20th World Congress of the International Society of Heart Research
  • Place of Presentation: Kyoto.
  • Year and Date: 20100513-20100516
• [Presentation] Blockade of T-Type Ca2+ Channel Prevents Sudden Death in Mice With Heart Failure. (2010)
  • Author(s): Kinoshita H, Kuwahara K, et al.
  • Organizer: 20th World Congress of the International Society of Heart Research
  • Place of Presentation: Kyoto.
  • Year and Date: 20100513-20100516
• [Presentation] Rho and actin dynamics-dependent nuclear translocation of MRTF-A is a common molecular mechanisms underlying both mechanical stretch- and neurohumoral stimulation-induced cardiac hypertrophy. (2010)
  • Author(s): Kuwahara K, et al.
  • Organizer: 14th Annual Scientific Session of the Society of Cardiovacular Endocrinology and Metabolism
  • Place of Presentation: Nara.
  • Year and Date: 20100331-20100401
• [Presentation] Angiotensin receptors signaling in cardiac remodeling. (2010)
  • Author(s): Kuwahara K, et al.
  • Organizer: 14th International Congress of Endocrinology.
  • Place of Presentation: 京都
  • Year and Date: 2010-03-28
• [Presentation] Functional inhibition of p300 affects the mitochondrial function and cell survival in the post-natal heart in mice. (2010)
  • Author(s): Nakagawa Y, Kuwahara K, et al.
  • Organizer: 14th International Congress of Endocrinology.
  • Place of Presentation: 京都
  • Year and Date: 2010-03-28
• [Presentation] Atrial and Brain Natriuretic Peptides-Guanylyl Cyclase-A Signaling Pathway Inhibits TRPC6-Mediated Pro-Hypertrophic Signaling in the Hearts. (2010)
  • Author(s): Kinoshita H, Kuwahara K, et al.
  • Organizer: 14th International Congress of Endocrinology.
  • Place of Presentation: 京都
  • Year and Date: 2010-03-28
• [Presentation] Blockade of T-Type Ca2+ Channel Corrects Cardiac Autonomic Nervous System Imbalance and Prevents Sudden Death in Mice With Heart Failure. (2010)
  • Author(s): Kuwabara Y, Kuwahara K, et al.
  • Organizer: 14th International Congress of Endocrinology.
  • Place of Presentation: 京都
  • Year and Date: 2010-03-28
• [Presentation] 心不全に対する新規治療標的の探索。 (2010)
  • Author(s): 桑原宏一郎。
  • Organizer: 第83回日本薬理学会年会。
  • Place of Presentation: 大阪。
  • Year and Date: 2010-03-16
• [Presentation] Inhibition of TRPC6 channel activity mediates the anti-hypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart。 (2010)
  • Author(s): 木下秀之、桑原宏一郎。
  • Organizer: The73rd Annual Scientific Meeting of The Japanese Circulation Society。
  • Place of Presentation: 京都。
  • Year and Date: 2010-03-07
• [Presentation] Myocardin-related transcription factor-A is a common mediator of mechanical stretch- and neurohumoral stimulation-induced hypertrophic response。 (2010)
  • Author(s): Kuwahara K, et al.
  • Organizer: The73rd Annual Scientific Meeting of The Japanese Circulation Society。
  • Place of Presentation: 京都
  • Year and Date: 2010-03-07
• [Presentation] Cardiac ntriuretic peptides inhibit TRPC6-mediated prohypertrophic signaling through cGMP-PKG pathway.. (2009)
  • Author(s): 木下秀之、桑原宏一郎。
  • Organizer: 4^<th> International Conference on cGMP.
  • Place of Presentation: ドイツ、Regensburg.
  • Year and Date: 2009-06-20
• [Presentation] 心臓内分泌代謝機能における転写共役因子の役割。 (2009)
  • Author(s): 桑原宏一郎。
  • Organizer: 第82回日本内分泌学会学術総会。
  • Place of Presentation: 群馬、前橋。
  • Year and Date: 2009-04-23
• [Presentation] ナトリウム利尿ペプチドの心保護作用におけるTRPC6の役割。 (2009)
  • Author(s): 木下秀之, 桑原宏一郎。
  • Organizer: 第82回日本内分泌学会学術総会。
  • Place of Presentation: 群馬、前橋。
  • Year and Date: 2009-04-23
• [Presentation] Transcriptional Pathways Regulating Caridac Remodeling. (2009)
  • Author(s): 桑原宏一郎。
  • Organizer: MRC international Symposia.
  • Place of Presentation: 韓国、光州
  • Year and Date: 2009-04-13
• [Presentation] MRTF-A, a rho-dependent co-activator of SRF, mediates mechanical stress-induced hypertrophic gene reprogramming. (2009)
  • Author(s): Kuwahara K, Olson EN, Nakao K.
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Scoiety.
  • Place of Presentation: 大阪市。
  • Year and Date: 2009-03-22
• [Presentation] Anovel NRSF-binding partner Zfp90 negatively regulates the repression activity of NRSF, a critical regulator of cardiac fetal gene program. (2009)
  • Author(s): Kuwahara K, Murakami M, Nakao K, et al.
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Scoiety.
  • Place of Presentation: 大阪市。
  • Year and Date: 2009-03-21
• [Presentation] Protein Kinase G-mediated inhibition of TRPC6 channel activity participates in anti-hypertrophic effect of cardiac natriuretic peptides. (2009)
  • Author(s): Kinoshita H, Kuwahara K, Nakao K, et al.
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Scoiety.
  • Place of Presentation: 大阪市。
  • Year and Date: 2009-03-20
• [Presentation] An imprtnt role fo p300 on mitochondrial gene expression and function and tolerance to ischemis in the heart. (2009)
  • Author(s): Nakagawa Y, Kuwahara K, Nakao K, et al.
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Scoiety.
  • Place of Presentation: 大阪市。
  • Year and Date: 2009-03-20
• [Presentation] T型カルシウムチャンネルは心不全モデルにおいて自律神経機能を介して、致死性不整脈発症に関与する。 (2008)
  • Author(s): 木下秀之、桑原宏一郎、中尾一和, 他。
  • Organizer: 第12回日本心血管内分泌代謝学会学術総会。
  • Place of Presentation: 熊本市。
  • Year and Date: 2008-11-28
• [Presentation] Blockade of T-type Ca2+ channel corrects imbalance in cardiac autonomic nerve activity and prevents sudden arrhythmic death in chronic heart failure in mice。 (2008)
  • Author(s): Kinoshita,K, Kuwahara K, et al.
  • Organizer: Basic Cardiovascular Science Conference 2008.
  • Place of Presentation: Keystone, Colorado. USA
  • Year and Date: 2008-08-18
• [Presentation] Inhibitory effect of p300. on cardiac mitochondrial gene expression and cell survival in postnatal heart. (2008)
  • Author(s): Nakagawa Y, Kuwahara K, et al.
  • Organizer: Basic Cardiovascular Science Conference 2008
  • Place of Presentation: Keystone Colorado. USA
  • Year and Date: 2008-07-29
• [Remarks] ホームページ等
  • URL: http://www.kuhp.kyoto-u.ac.jp/~med2/jpn/research/cardio.html