Professor Kinya Otsu MD PhD
BHF Professor of Cardiology
The James Black Centre
125 Coldharbour Lane
London SE5 9NU
Email: kinya.otsu@kcl.ac.uk
Biography
Professor Kinya Otsu graduated from Osaka University Medical School, Japan and received his MD in 1983. Following two years training in residency in Internal Medicine, he began his career in cardiovascular research at the National Institute of Health, USA (1984-1988) followed by the University of Toronto, Canada (1988-1991) and University of Nice, France (1991). Professor Otsu moved back to Japan as a Senior Resident in Cardiology at the Osaka University Hospital. He was appointed as Assistant Professor in 1997 and subsequently as Associate Professor of Cardiology in 2005 at the Osaka University Graduate School of Medicine. In 2012, he was recruited from Osaka to London as Professor of Cardiology at King's College London and became a BHF Chair of Cardiology. (Photograph; courtesy of BHF)
Research interests
Our group aims to integrate physiological, biochemical, cell biological, molecular and genetic approaches to study the pathogenesis of heart failure. Cardiomyocyte death plays an important role in the progression of cardiacremodelling. Neurohumoral factors and cytokinesthat are induced by mechanical stress on cardiomyocytes activatevarious intracellular signalling pathways, which regulate cell death. Our long term goal is to delineate the downstream mechanisms whereby activation of neurohumoral factors and cytokines mediate cardiomyocyte death and cardiac pathogenesis and to identify new therapeutic targets to treat patients with heart failure. In addition, it is an important question how cytokines are produced. Three types of cell death, namely apoptosis, necrosis and autophagic death, have been reported. We have worked on the roles of each of these types of cardiomyocyte death in the pathogenesis of heart failure.
The group’s work involves the complementary use of a variety of techniques such as genetic engineering including target construction and ES cell manipulation, establishment of disease models (pressure-overloaded heart failure, myocardial infarction, ischemia/reperfusion injury), hemodynamic analysis, echocardiography, immunohistochemistry, histology, confocal microscopy, electronmicroscopy, adult and neonatal cardiomyocyte isolation, cell culture, biochemical assays, DNA cloning and expression.
Recent research accomplishments
We have initially identified a novel intracellular signal transduction pathway in vitro, in which neurohumoral factors and cytokines activate a Pyk2-Rac1-reactive oxygen species-apoptosis signal regulating kinase 1 (ASK1)-p38/JNK-NF-kB signalling pathway. Then, we have identified the in vivo role of each of the molecules in the above signal transduction pathway, using a broad range of novel genetically modified models. Our results show that ASK1-JNK is involved in apoptosis, whereas p38 and NF-kB protect cells from stress. The balance between the two signalling pathways will determine cell fate.
Turning to necrosis, we made the significant finding that the mitochondria permeability transition pore is the responsible molecule to execute cardiomyocyte necrosis. When necrosis is adequately controlled, it is possible to avoid necrotic cardiomyocyte death in ischemia-reperfusion injury,
We then investigated the role of autophagy. We found that autophagy does not contribute to cardiomyocyte cell death during stress but is instead a mechanism to protect cells against lethal stress by maintaining the quality of proteins and organelles. In addition, we found that autophagy is necessary to prevent inflammatory responses in failing hearts.
Current and future research directions
The role of necrosis in the development of heart failure remains to be elucidated, although necrosis is a very important form of cell death. A major focus of our work is to identify in detail the entire mechanism of cardiomyocyte necrosis and elucidate its role in heart failure. In order to control necrosis or autophagy, we also aim to identify the upstream and downstream signalling transduction mechanisms regulating both these processes.
During our autophagy research, we realized the importance of “degradation systems” in the pathogenesis of heart failure. Cell fate is determined by balance between “synthesis” and “degradation”. However, the latter has been paid much less attention compared to the former. We therefore aim to elucidate the role of degradation of proteins, DNA, RNA and organelles such as mitochondria in the genesis of heart failure.
Group members
Senior Research Fellow
Postdoctoral Fellows
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Dr Minoru Takaoka
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Dr Shigemiki Omiya
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Dr Manabu Taneike
Research Associates
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Dr Noreen Shaikh
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Dr Elham Zarrinpashneh
Research Technician
PhD Student
Selected publications
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Y Okuno, A Nakamura-Ishizu, K Otsu, T Suda, Y Kubota . Pathological neoangiogenesis depends on oxidative stress regulation by ATM. (2012) Nature Medicine 18: 1208-1216.
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T Oka, S Hikoso, O Yamaguchi, M Taneike, T Takeda, T Tamai, J Oyabu, T Murakawa, H Nakayama, K Nishida, S Akira, A Yamamoto, I Komuro, K Otsu. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. (2012) Nature 485: 251–255.
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G Huang, Y Wang, P Vogel, T Kanneganti, K Otsu, H Chi:Signaling via the kinase p38a programs dendritic cells to drive TH17 differentiation and autoimmune inflammation (2012) Nature Immunol. 13:152-61.
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M Taneike, I Mizote, T Morita, T Watanabe, S Hikoso, O Yamaguchi, T Takeda, T Oka, T Tamai, J Oyabu, T Murakawa, H Nakayama, K Nishida, J Takeda, N Mochizuki, I Komuro, K Otsu. Calpain protects the heart from hemodynamic stress (2011) J Biol Chem. 286:32170-7.
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M Taneike, O Yamaguchi, A Nakai, S Hikoso, T Takeda, I Mizote, T Oka, T Tamai, J Oyabu, T Murakawa, K Nishida, T Shimizu, M Hori, I Komuro, T Shirasawa, N Mizushima, K Otsu: Inhibition of autophagy in the heart induces age-related cardiomyopathy (2010) Autophagy 6, 1-7.
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S Hikoso, O Yamaguchi, Y Nakano, T Takeda, S Omiya, I Mizote, M Taneike, T Oka, T Tamai, J Oyabu, Y Uno, Y Matsumura, K Nishida, K Suzuki, M Kogo, M Hori, K Otsu. The IkB kinase b/NF-kB signaling pathway protects the heart from hemodynamic stress mediated through the regulation of MnSOD expression (2009) Circ. Res. 105:70-9.
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Y Nishida, S Arakawa, K Fujitani, H Yamaguchi, T Mizuta, T Kanasaki, M Komatsu, K Otsu, Y Tsujimoto, S Shimizu. Discovery of Atg5/Atg7-independent alternative macroautophagy (2009) Nature 461:654-8.
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T Watanabe, T Takeda, S Omiya, S Hikoso, O Yamaguchi, Y Nakano, Y Higuchi, A Nakai, Y Abe, Y Aki-Jin, M Taniike, I Mizote, Y Matsumura, T Shimizu, K Nishida, K Imai, M Hori, T Shirasawa, K Otsu. Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure (2008) J Am Coll Cardiol. 52: 779-786.
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C Kim, Y Sano, K Todorova, BA Carlson, L Arpa, A Celada, T Lawrence, K Otsu, JL Brissette, J C Arthur, JM Park. p38alpha MAP kinase serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression (2008) Nature Immunol. 9:1019-27.
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M Taneike, O Yamaguchi, I Tsujimoto, S Hikoso, T Takeda, A Nakai, S Omiya, I Mizote, Y Nakano, Y Higuchi, Y Matsumura, K Nishida, M Hori, H Ichijo, K Otsu: Apoptosis signal-regulating kinase 1 (ASK1)/p38 signaling pathway negatively regulates physiological hypertrophy (2008) Circulation 117:545-552.
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A Nakai, O Yamaguchi, T Takeda, Y Higuchi, S Hikoso, M Taniike, S Omiya, I Mizote, Y Matsumura, M Asahi, K Nishida, M Hori, N Mizushima, K Otsu. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress (2007) Nature Medicine 13:619-624.
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H Kato, O Takeuchi, M Yamamoto, K Matsui, S Uematsu, A Jung, S Sato, T Kawai, O Yamaguchi, K Otsu, Yo Matsuura, M Yoneyama, T Fujita, T Tsujimura, CS Koh, CR Sousa, K Ishii, S Akira : Differential role of MDA5 and RIG-I in the recognition of RNA viruses (2006) Nature 441:101-5.
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T Takeda, M Asahi, O Yamaguchi, S Hikoso, H Nakayama, Y Kusakari, M Kawai, Y Higuchi, K Kashiwase, T Watanabe, M Taniike, A Nakai, K Nishida, S Kurihara, DB Donoviel, A Bernstein, T Tomita, T Iwatsubo, M Hori, K Otsu. Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling. (2005) FASEB J. 19(4): 2069-71.
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T Nakagawa, S Shimizu, T Watanabe, O Yamaguchi, K Otsu, H Yamagata, H Inohara, T Kubo, Y Tsujimoto: Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. (2005) Nature 434: 652-658.
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S Hikoso, O Yamaguchi, Y Higuchi, S Hirotani, T Takeda, K Kashiwase, T Watanabe, M Taniike, I Tsujimoto, M Asahi, Y Matsumura, K Nishida, H Nakajima, S Akira, M Hori, K Otsu: Pressure overload induces cardiac dysfunction and dilation in signal transducer and activator of transcription (STAT)6-deficient mice (2004) Circulation 110:2631-2637.
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K Nishida, O Yamaguchi, S Hirotani, S Hikoso, Y Higuchi, T Watanabe, T Takeda, S Osuka, T Morita, G Kondoh, Y Uno, K Kashiwase, M Taniike, A Nakai, Y Matsumura, J Miyazaki, T Sudo, K Hongo, Y Kusakari, S Kurihara, KR Chien, J Takeda, M Hori, K Otsu. p38a mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload (2004) Mol Cell Biol. 24:10611-10620.
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O Yamaguchi, T Watanabe,K Nishida,K Kashiwase, Y Higuchi, T Takeda, S Hikoso, S Hirotani, M Asahi, M Taniike, A Nakai, I Tsujimoto, Y Matsumura, J Miyazaki, KR Chien, A Matsuzawa, C Sadamitsu, H Ichijo, M Baccarini, M Hori, K Otsu: Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis (2004) J Clin Invest. 114:937-943.
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O Yamaguchi, Y Higuchi, S Hirotani, K Kashiwase, H Nakayama, S Hikoso, T Takeda, T Watanabe, M Asahi, M Taniike, Y Matsumura, I Tsujimoto, K Hongo, Y Kusakari, S Kurihara, K Nishida, H Ichijo, M Hori, K Otsu: Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling (2003) Proc Natl Acad Sci USA. 100:15883-15888.
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S Hirotani, K Otsu, K Nishida, Y Higuchi, T Morita, H Nakayama, O Yamaguchi, T Mano, Y Matsumura, H Ueno, M Tada, M Hori : Involvement of nuclear factor-kB and apoptosis signal-regulating kinase 1 in G-Protein-coupled receptor agonist-induced cardiomyocyte hypertrophy (2002) Circulation 105:509-515.