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Research on the Mechanisms of Hypertrophic and Dilated Cardiomyopathies and Potential Therapies

Cardiomyopathies can have their origins in viral infections, toxicosis, immune reactions and inherited gene mutations, and are characterized by contractile and relaxation impairment that lead to heart failure. Impairment in the contractile mechanisms of sarcomeric proteins and calcium handling are thought to be the main factors involved. In our department we are investigating both hypertrophic (HCM) and dilated cardiomyopathies (DCM) from various perspectives. One focus of this research is cardiomyopathies caused by inherited single gene mutations in cardiac troponin T.

We developed knockin mouse models, by inserting human gene mutations in cardiac troponin T into the mouse genome (Collaboration with Kyushu University), which are characterized by many of the symptoms of human cardiomyopathies. Utilising these mouse models we are now shedding light on how calcium regulatory mechanisms, abnormal microvascular function and abnormal cardiac autonomic neural regulation contribute to the progression of myofilament contractile dysfunction in HCM and DCM.

Related Publications

  1. 遺伝性拡張型心筋症に対する新規治療法の開発に向けて. 戦 冬雲、杜 成坤、森本 幸生、秋山 剛、Daryl O. Schwenke、細田 洋司、寒川 賢治、白井 幹康、Pearson James. BIO Clinica31 (6):101-104, 2016.
  2. Mohamed R., S. Morimoto, I. Ibrahim, D-Y. Zhan, C-K. Du, M. Arioka, T. Yoshihara, F. Takahashi-Yanaga, T. Sasaguri. GSK3β heterozygous knockout is cardioprotective in a knock-in mouse model of familial dilated cardiomyopathy. American Journal of Physiology (Heart and Circulatory Physiology) doi: 10.1152/ajpheart.00771. Apr, 2016
  3. 生理活性ペプチドを用いた拡張型心筋症の新規治療法の開発. 戦 冬雲, 杜 成坤, 秋山 剛, 白井 幹康. Medical Science Digest. 41(13):476-479, 2015
  4. Du C-K., D-Y. Zhan, S. Morimoto. In vivo effects of propyl gallate, a novel Ca2+ sensitizer, in a mouse model of dilated cardiomyopathy caused by cardiac troponin T mutation. Life Sciences 109:15-19, 2014.
  5. Du C.K., D.Y. Zhan, S. Morimoto, T. Akiyama, D.O. Schwenke, H. Hosoda, K. Kangawa and M. Shirai. Survival benefit of ghrelin in the heart failure due to dilated cardiomyopathy. Pharmacol Res Perspect 5, e00064, 2014.
  6. Fan X., F. Takahashi-Yanaga, S. Morimoto, D-Y. Zhan, K. Igawa, K. Tomooka, and T. Sasaguri. Celecoxib and 2, 5-Dimethyl-Celecoxib prevent cardiac remodeling inhibiting Akt-mediated signal transduction in an inherited dilated cardiomyopathy mouse model. The Journal of Pharmacology and Experimental Therapeutics, 338(1):2-11, 2011.
  7. Arimura T., R. Sato, N. Machida, H. Bando, D-Y. Zhan, S. Morimoto, R. Tanaka, Y. Yanmane, G. Bonne and A. Kimura. Improvement of left ventricular dysfunction and survival prognosis of dilated cardiomyopathy by administration of calcium sensitizer SCH00013 in a mouse model. Journal of the American College Cardiology. 55(14):1503-1505, 2010.
  8. Sfichi-Duke L., M.L. Garcia-Cazarin, C. Amelia Sumandea, G.A. Sievert, C.W. Balke, D-Y. Zhan, S. Morimoto and M.P. Sumandea. Cardiomyopathy-causing deletion K210 in cardiac troponin T affects phosphorylation propensity of sarcomeric proteins. Journal of Molecular & Cellular Cardiology. 48(5):934-942, 2010.
  9. Wang Y-Y., S. Morimoto, C-K. Du, Q-W. Lu, D-Y. Zhan, T. Tsutsumi, T. Ide, Y. Miwa, F. Takahashi-Yanaga and T. Sasaguri. Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy. Cardiovascular Research. 87(4):636-646, 2010.
  10. Toko H., H. Takahashi, Y. Kayama, T. Oka, T. Minamino, S. Okada, S. Morimoto, D-Y. Zhan, F. Terasaki, M.E. Anderson, M. Inoue, A. Yao, R. Nagai, Y. Kitaura, T. Sasaguri and I. Komuro. Ca2+ Calmodulin-dependent kinase Ⅱ causes heart failure by accumulation of p53 in dilated cardiomyopathy. Circulation. 122:891-899, 2010.
  11. Du C-K., S. Morimoto, K. Nishii, R. Minakami, M. Ohta, N. Tadano, Q-W. Lu, Y-Y. Wang, D-Y. Zhan, M. Mochizuki, S. Kita, Y. Miwa, F. Takahashi-Yanaga, T. Iwamoto, I. Ohtsuki, and T. Sasaguri. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation. Circulation Research. 101(2):185-194, 2007.
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