Organization
School of Medicine Medical Course Basic Medicine Physiology[Autonomous Function]
External link
IRIBE Gentaro
Degree
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博士（医学） ( オックスフォード大学（英国） )
Research Interests
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mechano-electric coupling
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心臓力学
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mechano-electric coupling
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cardiac mechanics
Research Areas
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Life Science / Physiology
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Life Science / Clinical pharmacy
Education
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University of Oxford
- 2007
Country： United Kingdom
Research History
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Asahikawa Medical College Dept. Physiology Professor
2019
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岡山大学医歯薬学総合研究科 准教授
2016 - 2019
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Associate Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University
2016
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岡山大学医歯薬学総合研究科 講師
2013 - 2016
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Senior Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University
2013 - 2016
Professional Memberships
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日本生理学会
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日本生物物理学会
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日本循環制御医学会
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日本生体医工学会
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米国生物物理学会（Biophysical Society）
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ヨーロッパ心臓病学会（European Society of Cardiology）
Committee Memberships
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日本生体医工学会 代議員
2015
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日本生理学会 評議員
2014
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ヨーロッパ心臓病学会（European Society of Cardiology） フェロー（FESC）
2009
Papers
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Role of purinergic activation and TRPC3 channels in the Frank-Starling mechanism Reviewed
Yumiko Chiba, Keiko Kaihara, Gentaro Iribe
The Journal of Physiological Sciences 76 ( 1 ) 100052 - 100052 2026.3
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Stretch‐induced reactive oxygen species contribute to the Frank–Starling mechanism Reviewed
Keiko Kaihara, Hiroaki Kai, Yumiko Chiba, Keiji Naruse, Gentaro Iribe
The Journal of Physiology 602 ( 18 ) 4347 - 4362 2024.9
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Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors Reviewed
Sayaka Oda, Kazuhiro Nishiyama, Yuka Furumoto, Yohei Yamaguchi, Akiyuki Nishimura, Xiaokang Tang, Yuri Kato, Takuro Numaga-Tomita, Toshiyuki Kaneko, Supachoke Mangmool, Takuya Kuroda, Reishin Okubo, Makoto Sanbo, Masumi Hirabayashi, Yoji Sato, Yasuaki Nakagawa, Koichiro Kuwahara, Ryu Nagata, Gentaro Iribe, Yasuo Mori, Motohiro Nishida
Nature Communications 13 ( 1 ) 2022.10
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High hydrostatic pressure induces slow contraction in mouse cardiomyocytes. Reviewed International journal
Yohei Yamaguchi, Masayoshi Nishiyama, Hiroaki Kai, Toshiyuki Kaneko, Keiko Kaihara, Gentaro Iribe, Akira Takai, Keiji Naruse, Masatoshi Morimatsu
Biophysical journal 2022.7
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Rémi Peyronnet, Olga Solovyova, Gentaro Iribe, Leonid B. Katsnelson
Frontiers in Physiology 12 2021.4
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Ischemia Enhances the Acute Stretch-Induced Increase in Calcium Spark Rate in Ventricular Myocytes Reviewed
Breanne A. Cameron, Hiroaki Kai, Keiko Kaihara, Gentaro Iribe, T. Alexander Quinn
Frontiers in Physiology 11 2020.4
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The Effects of Mechanical Preload on Transmural Differences in Mechano-Calcium-Electric Feedback in Single Cardiomyocytes: Experiments and Mathematical Models Reviewed
Anastasia Khokhlova, Pavel Konovalov, Gentaro Iribe, Olga Solovyova, Leonid Katsnelson
Frontiers in Physiology 11 2020.3
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L-type calcium channel modulates mechanosensitivity of the cardiomyocyte cell line H9c2. Reviewed International journal
Ken Takahashi, Shogo Hayashi, Mari Miyajima, Marei Omori, Jing Wang, Keiko Kaihara, Masatoshi Morimatsu, Chen Wang, Jian Chen, Gentaro Iribe, Keiji Naruse, Masahiro Sokabe
Cell calcium 79 68 - 74 2019.5
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Transmural cellular heterogeneity in myocardial electromechanics Reviewed
Anastasia Khokhlova, Nathalie Balakina-Vikulova, Leonid Katsnelson, Gentaro Iribe, Olga Solovyova
Journal of Physiological Sciences 68 ( 4 ) 387 - 413 2018.7
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TRPC3 participates in angiotensin II type 1 receptor-dependent stress-induced slow increase in intracellular Ca2+ concentration in mouse cardiomyocytes Reviewed
Yohei Yamaguchi, Gentaro Iribe, Toshiyuki Kaneko, Ken Takahashi, Takuro Numaga-Tomita, Motohiro Nishida, Lutz Birnbaumer, Keiji Naruse
Journal of Physiological Sciences 68 ( 2 ) 153 - 164 2018.3
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The effects of load on transmural differences in contraction of isolated mouse ventricular cardiomyocytes Reviewed
Anastasia Khokhlova, Gentaro Iribe, Leonid Katsnelson, Keiji Naruse, Olga Solovyova
Journal of Molecular and Cellular Cardiology 114 276 - 287 2018.1
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Role of TRPC3 and TRPC6 channels in the myocardial response to stretch: Linking physiology and pathophysiology Reviewed
Yohei Yamaguchi, Gentaro Iribe, Motohiro Nishida, Keiji Naruse
Progress in Biophysics and Molecular Biology 130 ( Pt B ) 264 - 272 2017.11
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Effects of simulated ischemia on the transmural differences in the Frank–Starling relationship in isolated mouse ventricular cardiomyocytes Reviewed
Anastasia Khokhlova, Gentaro Iribe, Yohei Yamaguchi, Keiji Naruse, Olga Solovyova
Progress in Biophysics and Molecular Biology 130 ( Pt B ) 323 - 332 2017.11
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Mechano-sensitivity of mitochondrial function in mouse cardiac myocytes Reviewed
Gentaro Iribe, Keiko Kaihara, Yohei Yamaguchi, Michio Nakaya, Ryuji Inoue, Keiji Naruse
Progress in Biophysics and Molecular Biology 130 ( Pt B ) 315 - 322 2017.11
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Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches Reviewed
Yaopeng Hu, Yubin Duan, Ayako Takeuchi, Lin Hai-Kurahara, Jun Ichikawa, Keizo Hiraishi, Tomohiro Numata, Hiroki Ohara, Gentaro Iribe, Michio Nakaya, Masayuki X. Mori, Satoshi Matsuoka, Genshan Ma, Ryuji Inoue
CARDIOVASCULAR RESEARCH 113 ( 10 ) 1243 - 1255 2017.8
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Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction Reviewed
Michio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, Hitoshi Kurose
JOURNAL OF CLINICAL INVESTIGATION 127 ( 1 ) 383 - 401 2017.1
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Effects of Bepridil on Stretch-Activated BKca Channels and Stretch-Induced Extrasystoles in Isolated Chick Hearts Reviewed
H. Jin, G. Iribe, K. Naruse
PHYSIOLOGICAL RESEARCH 66 ( 3 ) 459 - 465 2017
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Transmural Differences in Mechanical Properties of Isolated Subendocardial and Subepicardial Cardiomyocytes Reviewed
A. D. Khokhlova, G. Iribe
BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE 162 ( 1 ) 48 - 50 2016.11
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心筋の伸展刺激誘発性の活性酸素産生増加における呼吸鎖複合体の役割(Role of respiratory chain complexes in myocardial stretch-induced increase in reactive oxygen species)
Kaihara Keiko, Naruse Keiji, Iribe Gentaro
The Journal of Physiological Sciences 66 ( Suppl.1 ) S97 - S97 2016.3
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Celsior preserves cardiac mechano-energetics better than University of Wisconsin solution by preventing oxidative stress Reviewed
Takahiko Kiyooka, Yu Oshima, Waso Fujinaka, Gentaro Iribe, Juichiro Shimizu, Satoshi Mohri, Kazufumi Nakamura
INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 22 ( 2 ) 168 - 175 2016.2
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Effects of axial stretch on mitochondrial reactive oxygen species in cardiac myocytes Reviewed
Gentaro Iribe, Keiko Kaihara, Keiji Naruse
Transactions of Japanese Society for Medical and Biological Engineering 52 44 2014.8
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Load dependency in force-length relations in isolated single cardiomyocytes Reviewed
Gentaro Iribe, Toshiyuki Kaneko, Yohei Yamaguchi, Keiji Naruse
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY 115 ( 2-3 ) 103 - 114 2014.8
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Energy for Myocardial Ca2+ handling per beat increases with heart rate in excised cross-circulated canine heart Reviewed
Takahiko Kiyooka, Yu Oshima, Waso Fujinaka, Gentaro Iribe, Satoshi Mohri, Juichiro Shimizu
Tokai Journal of Experimental and Clinical Medicine 39 ( 1 ) 51 - 58 2014
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Effects of Propofol on Left Ventricular Mechanoenergetics in the Excised Cross-circulated Canine Heart Reviewed
Waso Fujinake, Juichiro Shimizu, Gentaro Iribe, Takeshi Imaoka, Yu Oshima, Takahiko Kiyooka, Kiyoshi Morita, Satoshi Mohri
ACTA MEDICA OKAYAMA 66 ( 6 ) 435 - 442 2012.12
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Aberrant Calcium Handling Inhibits Functional Maturation and Excitation in Factors-based Human Cardiomyocytes Differentiation Reviewed
Suguru Tarui, Junko Kobayashi, Masataka Hirata, Ken Takahashi, Gentaro Iribe, Keiji Naruse, Shingo Kasahara, Shunji Sano, Hidemasa Ou
Journal of Cardiac Failure 18 ( 10 ) S146 2012.10
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Role of Sarcolemmal BKCa Channels in Stretch-Induced Extrasystoles in Isolated Chick Hearts Reviewed
Gentaro Iribe, Honghua Jin, Keiji Naruse
CIRCULATION JOURNAL 75 ( 11 ) 2552 - 2558 2011.11
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Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing Reviewed
T. A. Quinn, S. Granite, M. A. Allessie, C. Antzelevitch, C. Bollensdorff, G. Bub, R. A. B. Burton, E. Cerbai, P. S. Chen, M. Delmar, D. DiFrancesco, Y. E. Earm, I. R. Efimov, M. Egger, E. Entcheva, M. Fink, R. Fischmeister, M. R. Franz, A. Garny, W. R. Giles, T. Hannes, S. E. Harding, P. J. Hunter, G. Iribe, J. Jalife, C. R. Johnson, R. S. Kass, I. Kodama, G. Koren, P. Lord, V. S. Markhasin, S. Matsuoka, A. D. McCulloch, G. R. Mirams, G. E. Morley, S. Nattel, D. Noble, S. P. Olesen, A. V. Panfilov, N. A. Trayanova, U. Ravens, S. Richard, D. S. Rosenbaum, Y. Rudy, F. Sachs, F. B. Sachse, D. A. Saint, U. Schotten, O. Solovyova, P. Taggart, L. Tung, A. Varro, P. G. Volders, K. Wang, J. N. Weiss, E. Wettwer, E. White, R. Wilders, R. L. Winslow, P. Kohl
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY 107 ( 1 ) 4 - 10 2011.10
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Effects of axial stretch on sarcolemmal BKCa channels in post-hatch chick ventricular myocytes Reviewed
Gentaro Iribe, Honghua Jin, Keiko Kaihara, Keiji Naruse
EXPERIMENTAL PHYSIOLOGY 95 ( 6 ) 699 - 711 2010.6
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Axial Stretch of Rat Single Ventricular Cardiomyocytes Causes an Acute and Transient Increase in Ca2+ Spark Rate Reviewed
Gentaro Iribe, Christopher W. Ward, Patrizia Camelliti, Christian Bollensdorff, Fleur Mason, Rebecca A. B. Burton, Alan Garny, Mary K. Morphew, Andreas Hoenger, W. Jonathan Lederer, Peter Kohl
CIRCULATION RESEARCH 104 ( 6 ) 787 - U141 2009.3
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Axial stretch enhances sarcoplasmic reticulum Ca2+ leak and cellular Ca2+ reuptake in guinea pig ventricular myocytes: Experiments and models Reviewed
Gentaro Iribe, Peter Kohl
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY 97 ( 2-3 ) 298 - 311 2008.6
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Force-length relations in isolated intact cardiomyocytes subjected to dynamic changes in mechanical load Reviewed
Gentaro Iribe, Michiel Helmes, Peter Kohl
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 292 ( 3 ) H1487 - H1497 2007.3
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Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations: a modelling study Reviewed
G Iribe, P Kohl, D Noble
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES 364 ( 1842 ) 1107 - 1133 2006.5
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Celsior preserved cardiac mechanoenergetics better than popular solutions in canine hearts Reviewed
Y Oshima, S Mohri, J Shimizu, G Iribe, T Imaoka, W Fujinaka, T Kiyooka, K Ishino, S Sano, F Kajiya, H Suga
ANNALS OF THORACIC SURGERY 81 ( 2 ) 658 - 664 2006.2
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Normal distribution of ventricular pressure-volume area of arrhythmic beats under atrial fibrillation in canine heart Reviewed
S Mohri, J Shimizu, G Iribe, H Ito, T Morita, H Yamaguchi, S Sano, F Kajiya, H Suga
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 288 ( 4 ) H1740 - H1746 2005.4
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Predictability of O-2 consumption from contractility and mechanical energy of absolute arrhythmic beats in canine heart Reviewed
J Shimizu, S Mohri, G Iribe, H Ito, T Morita, H Yamaguchi, S Sano, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 55 ( 2 ) 135 - 142 2005.4
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Arterial and left ventricular pressures illude transient alternans of contractility during postextrasystolic potentiation Reviewed
G Iribe, J Shimizu, S Mohri, Y Syuu, T Imaoka, T Kiyooka, J Araki, Y Kanmura, F Kajiya, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 54 ( 4 ) 373 - 383 2004.8
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Sarcomere-length dependence of lattice volume and radial mass transfer of myosin cross-bridges in rat papillary muscle Reviewed
N Yagi, H Okuyama, H Toyota, J Araki, J Shimizu, G Iribe, K Nakamura, S Mohri, K Tsujioka, H Suga, F Kajiya
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 448 ( 2 ) 153 - 160 2004.5
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Postextrasystolic Contractility normally decays in alternans in canine in situ heart Reviewed
J Shimizu, S Mohri, G Iribe, Y Kitagawa, H Ito, J Araki, M Takaki, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 53 ( 4 ) 313 - 318 2003.8
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Exponential fitting of postextrasystolic potentiation may underestimate the cardiac Ca2+ recirculation fraction: A theoretical analysis Reviewed
Y Doi, J Araki, W Fujinaka, T Kiyooka, Y Oshima, G Iribe, J Shimizu, K Morita, F Kajiya, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 53 ( 2 ) 89 - 96 2003.4
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An X-ray diffraction study on contraction of rat papillary muscle with different afterloads Reviewed
H Okuyama, N Yagi, H Toyota, J Araki, J Shimizu, G Iribe, K Nakamura, S Mohri, M Kakishita, K Hashimoto, T Morimoto, K Tsujioka, F Kajiya, H Suga
MOLECULAR AND CELLULAR ASPECTS OF MUSCLE CONTRACTION 538 533 - 539 2003
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Frequency distribution, variance, and moving average of left ventricular rhythm and contractility during atrial fibrillation in dog Reviewed
T Morita, J Araki, Y Oshima, H Mitani, G Iribe, S Mohri, J Shimizu, S Sano, F Kajiya, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 52 ( 1 ) 41 - 49 2002.2
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Frank-Starling mechanism retains recirculation fraction of myocardial Ca2+ in the beating heart Reviewed
J Mizuno, J Araki, S Mohri, H Minami, Y Doi, W Fujinaka, K Miyaji, T Kiyooka, Y Oshima, G Iribe, M Hirakawa, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 51 ( 6 ) 733 - 743 2001.12
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ASSESMENT OF TOTAL CA(2+) HANDLING FOR EXCITATION-CONTRACTION COUPLING IN BEATING LEFT VENTRICLE Reviewed
Junichi Araki, Juichiro Shimizu, Gentaro Iribe, Satoshi Mohri, Takahiko Kiyooka, Yu Osima, Waso Fujinaka, Yumiko Doi, Hiroyuki Suga
JOURNAL OF MECHANICS IN MEDICINE AND BIOLOGY 1 ( 2 ) 123 - 138 2001.10
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New calculation of internal Ca2+ recirculation fraction from alternans decay of postextrasystolic potentiation Reviewed
G Iribe, J Araki, S Mohri, J Shimizu, T Imaoka, Y Kanmura, F Kajiya, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 51 ( 2 ) 143 - 149 2001.4
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Coupling interval from slow to tachycardiac pacing decides sustained alternans pattern Reviewed
S Suzuki, J Araki, Y Doi, W Fujinaka, H Minami, G Iribe, S Mohri, J Shimizu, M Hirakawa, H Suga
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 280 ( 3 ) H1368 - H1375 2001.3
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Total Ca2+ handling for E-C coupling in the whole heart: An integrative analysis Reviewed
J Araki, S Mohri, G Iribe, J Shimizu, H Suga
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 79 ( 1 ) 87 - 92 2001.1
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Crossbridge dynamics examined by X-ray diffraction in cardiac muscle
Okuyama Hiroshi, Yagi Naoto, Toyota Hiroko, Araki Junichi, Mohri Satoshi, Iribe Gentaro, Imaoka Takeshi, Tsujioka Katsuhiko, Suga Hiroyuki
The 13<sup>th</sup> bioengineering conference 2000 annual meeting of BE D/JSME 36-37 2001
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2,3-Butanedione monoxime suppresses primarily total calcium handling in canine heart Reviewed
M Maesako, J Araki, S Lee, Y Doi, T Imaoka, G Iribe, S Mohri, M Hirakawa, M Harada, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 50 ( 5 ) 543 - 551 2000.10
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Postextrasystolic contractile decay always contains exponential and alternans components in canine heart Reviewed
J Shimizu, J Araki, G Iribe, T Imaoka, S Mohri, K Kohno, H Matsubara, T Ohe, M Takaki, H Suga
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 279 ( 1 ) H225 - H233 2000.7
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Energy-wasteful total Ca2+ handling underlies increased O-2 cost of contractility in canine stunned heart Reviewed
SY Lee, J Araki, T Imaoka, M Maesako, G Iribe, K Miyaji, S Mohri, J Shimizu, M Harada, T Ohe, M Hirakawa, H Suga
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 278 ( 5 ) H1464 - H1472 2000.5
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Mechanoenergetics characterizing oxygen wasting effect of caffeine in canine left ventricle Reviewed
T Takasago, Y Goto, K Hata, A Saeki, T Nishioka, TW Taylor, G Iribe, S Mohri, J Shimizu, J Araki, H Suga
JAPANESE JOURNAL OF PHYSIOLOGY 50 ( 2 ) 257 - 265 2000.4
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Effects of the phosphodiesterase III inhibitors olprinone, milrinone, and amrinone on hepatosplanchnic oxygen metabolism Reviewed
G Iribe, H Yamada, A Matsunaga, N Yoshimura
CRITICAL CARE MEDICINE 28 ( 3 ) 743 - 748 2000.3
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Anesthetic management for a patient with mental retardation and unexamined complex congenital heart disease Reviewed
G. Iribe, K. Yoshimine, A. Takehara, M. Masuda, T. Omae, M. Kamihashi
Japanese Journal of Anesthesiology 49 ( 10 ) 1145 - 1147 2000
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Effect of prostaglandin E1 and nitroglycerin on portal venous flow during hypothermic extracorporeal circulation: Assessment by transesophageal echography Reviewed
G Iribe, Y Ohnishi, Y Hayashi, M Kuro
ACTA ANAESTHESIOLOGICA SCANDINAVICA 43 ( 5 ) 520 - 525 1999.5
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Total Ca handling in canine mild Ca overload failing heart Reviewed
J Mizuno, J Araki, G Iribe, M Maesako, T Morita, K Miyaji, T Imaoka, S Mohri, S Sano, T Ohe, M Hirakawa, H Suga
HEART AND VESSELS 14 ( 1 ) 38 - 51 1999
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Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation: simulation Reviewed
S Mohri, J Araki, T Imaoka, G Iribe, M Maesako, J Shimizu, H Matsubara, T Ohe, M Hirakawa, H Suga
HEART AND VESSELS 14 ( 2 ) 82 - 89 1999
Books
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Biological, Physical and Technical Basics of Cell Engineering.
（Development in Cell Manipulation Techniques for the Study of Single Cardiomyocyte Mechanics.）
Springer 2018
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Cardiac mechano-electric coupling and arrhythmias. 2nd edition
（Non-sarcolemmal stretch-activated channels.）
Oxford University Press 2011
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バイオテクノロジーシリーズ 細胞分離・操作技術の最前線
(株)シーエムシー 2008
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細胞分離・操作技術の最前線
シーエムシー出版 2008
MISC
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Myocardial stretch-induced ROS production was increased via inter-organ network
千葉弓子, 古部瑛莉子, 田中宏樹, 山本幸司, 入部玄太郎
日本解剖学会総会・全国学術集会抄録集(CD-ROM) 130th 2025
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心筋の伸展刺激誘発性ROS産生のメカノトランスダクション
千葉弓子, 貝原恵子, 入部玄太郎
日本生体医工学会大会プログラム・抄録集(Web) 63rd 2024
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Single cell mechanics of human cardiomyocytes assessed by cellular force-length relationships(タイトル和訳中)
Komatsu Hiroaki, Kotani Yasuhiro, Kaihara Keiko, Naruse Keiji, Kasahara Shingo, Iribe Gentaro
The Journal of Physiological Sciences 73 ( Suppl.1 ) 108 - 108 2023.5
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Yamaguchi Yohei, Kaneko Toshiyuki, Iribe Gentaro, Ohya Susumu
Proceedings for Annual Meeting of The Japanese Pharmacological Society 97 2-B-P-006 2023
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マウス心筋細胞におけるTRPC6による力学特性の制御機構
山口陽平, 金子智之, 成瀬恵治, 大矢進, 入部玄太郎
トランスポーター研究会年会抄録集 17th (Web) 2023
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マウス心室心筋細胞におけるNOX4-TRPV1相互作用の単一細胞力学に対する役割(Role of NOX4-TRPV1 interaction on single cell mechanics in mouse ventricular cardiomyocytes)
Kaihara Keiko, Naruse Keiji, Iribe Gentaro
The Journal of Physiological Sciences 72 ( Suppl.1 ) 117 - 117 2022.12
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NOX4由来のROSが心筋細胞メカニクスに及ぼす影響(Effects of NOX4-induced ROS on single cell mechanics in mouse ventricular cardiomyocytes)
Kaihara Keiko, Naruse Kenji, Iribe Gentaro
The Journal of Physiological Sciences 71 ( Suppl.1 ) 163 - 163 2021.8
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Intracellular Calcium Concentration-independent Cardiomyocyte Contraction Triggered by High Hydrostatic Pressure
Yohei Yamaguchi, Masayoshi Nishiyama, Gentaro Iribe, Keiji Naruse, Masatoshi Morimatsu
Biophysical Journal 120 ( 3 ) 67a - 68a 2021.2
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マウスにおいてNADPHオキシダーゼ4が心筋細胞メカニクスに及ぼす影響(Effects of NADPH oxidase (NOX) 4 on single cell mechanics in mouse ventricular cardiomyocytes)
Kaihara Keiko, Naruse Keiji, Iribe Gentaro
The Journal of Physiological Sciences 70 ( Suppl.1 ) S119 - S119 2020.3
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Role of TRPC6 on Single Cell Mechanics in Mouse Cardiomyocytes
Yohei Yamaguchi, Gentaro Iribe, Keiji Naruse, Akira Takai
Biophysical Journal 118 ( 3 ) 415a - 415a 2020.2
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Involvement of myocardial acute stretch-induced ROS production in development of heart failure
KAIHARA Keiko, NARUSE Keiji, IRIBE Gentaro
日本生体医工学会大会プログラム・抄録集(Web) 59th 2020
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心筋細胞におけるストレッチ誘発性ミトコンドリア過分極に関するパネキシンヘミチャネルの役割(Role of pannexin hemichannel on stretch-induced mitochondrial hyperpolarization in cardiomyocytes)
Katsura Daisuke, Iribe Gentaro, Kaihara Keiko, Naruse Keiji
The Journal of Physiological Sciences 69 ( Suppl.1 ) S202 - S202 2019.6
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心筋細胞メカニクスにNADPHオキシダーゼ4が及ぼす影響(Single cell mechanics effects of NADPH oxidase(NOX) 4 in mouse ventricular cardiomyocytes)
Kaihara Keiko, Iribe Gentaro, Kai Hiroaki, Naruse Keiji
生物物理 58 ( Suppl.1-2 ) S431 - S431 2018.8
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伸展刺激誘発性の活性酸素がマウス心筋calciumハンドリングに及ぼす影響(Effects of stretch-induced reactive oxygen species on calcium handling in mouse ventricular cardiomyocytes)
Kai Hiroaki, Iribe Gentaro, Kaihara Keiko, Yamaguchi Yohei, Naruse Keiji
The Journal of Physiological Sciences 68 ( Suppl.1 ) S142 - S142 2018.3
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伸展刺激誘発性活性酸素がマウス心室心筋細胞の単細胞機構に及ぼす影響(Effects of stretch-induced reactive oxygen species on single cell mechanics in mouse ventricular cardiomyocytes)
Kaihara Keiko, Iribe Gentaro, Hayama Yohei, Kai Hiroaki, Naruse Keiji
The Journal of Physiological Sciences 68 ( Suppl.1 ) S118 - S118 2018.3
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Single cell mechanics effects of NADPH oxidase (NOX) 4 in mouse ventricular cardiomyocytes
KAIHARA Keiko, IRIBE Gentaro, KAI Hiroaki, NARUSE Keiji
生物物理(Web) 58 ( Supplement 1-2 ) 2018
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貝原 恵子, 成瀬 恵治, 入部 玄太郎
日本生理学雑誌 79 ( 1 ) 42 - 43 2017.2
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Application of mechanobiological engineering to regenerative and reproductive medicine Invited
Takahashi K, Oh H, Iribe G, Matsuura K, Naruse K
Trans JSMBE 55 ( 4PM-Abstract ) 340 2017
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心筋細胞におけるTRPC3を介した伸展刺激感知機構(TRPC3 contributes to a slow force response to stretch on mice cardiomyocytes)
Yamaguchi Yohei, Iribe Gentaro, Kaihara Keiko, Naruse Keiji
The Journal of Physiological Sciences 66 ( Suppl.1 ) S76 - S76 2016.3
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Transmural Differences in Preload-Dependency of CA(2+) Transients in Isolated Cardiomyocytes
Anastasia Khokhlova, Gentaro Iribe, Olga Solovyova
BIOPHYSICAL JOURNAL 110 ( 3 ) 99A - 99A 2016.2
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Speculation of localization of TRPC3 using in vitro and in silico experiments
Yamaguchi Yohei, Iribe Gentaro, Naruse Keiji
Transactions of Japanese Society for Medical and Biological Engineering 54 ( 28 ) S395 - S395 2016
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統合生理学的手法によるマウス心筋細胞TRPC3チャネルの局在部位推定
山口陽平, 入部玄太郎, 成瀬恵治
日本生理学雑誌(Web) 78 ( 1 ) 2016
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Load-dependency in mechanical properties of subepicardial and subendocardial cardiomyocytes
Anastasia Khokhlova, Gentaro Iribe, Olga Solovyova
Computing in Cardiology 42 965 - 968 2015.2
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Development of a Fluidic Gripper for Isolated Cardiomyocytes Reviewed
Yohei Yamaguchi, Yasuyo Yamaguchi, Shuichi Wakimoto, Gentaro Iribe, Keiji Naruse
Proc. of The 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society 110 - 110 2015
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Macro-micro integration in cardiac mechanics and electrophysiology by computational biology
IRIBE GENTARO, NARUSE KEIJI
Transactions of Japanese Society for Medical and Biological Engineering 53 S139_02 - S139_02 2015
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伸展刺激によるカルシウムスパーク増加におけるミトコンドリアの役割(Role of mitochondria on stretch-induced increase in calcium spark rate)
Kaihara Keiko, Naruse Keiji, Iribe Gentaro
The Journal of Physiological Sciences 64 ( Suppl.1 ) S129 - S129 2014.3
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Involvement of TRPC in the Slow Force Response Observed in Mouse Ventricular Myocytes
Yohei Yamaguchi, Toshiyuki Kaneko, Keiji Naruse, Gentaro Iribe
BIOPHYSICAL JOURNAL 106 ( 2 ) 772A - 772A 2014.1
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1107 Fluidic Micro gripper for grasping a cardiomyocyte
KAI Toshiaki, WAKIMOTO Shuichi, YAMAMOTO Yohta, SUZUMORI Koichi, KANEKO Toshiyuki, IRIBE Gentaro
The Proceedings of the Machine Design and Tribology Division meeting in JSME 2014.14 33 - 34 2014
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伸展刺激誘発性カルシウムスパーク増加におけるミトコンドリアの役割
貝原恵子, 成瀬恵治, 入部玄太郎
日本生理学雑誌 76 ( 4 (Web) ) 2014
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Effect of azelnidipine and amlodipine on single cell mechanics in mouse cardiomyocytes
Gentaro Iribe, Keiko Kaihara, Hiroshi Ito, Keiji Naruse
EUROPEAN JOURNAL OF PHARMACOLOGY 715 ( 1-3 ) 142 - 146 2013.9
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Iribe Gentaro, Kaneko Toshiyuki, Yamaguchi Yohei, Kaihara Keiko, Naruse Keiji
BME 51 M - 32-M-32 2013
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Factors-based Human Cardiomyocytes Differentiation Exhibits Defective Maturation and Excitation Through Aberrant Calcium Handling Proteins
Suguru Tarui, Junko Kobayashi, Masataka Hirata, Ken Takahashi, Gentaro Iribe, Keiji Naruse, Shingo Kasahara, Shunji Sano, Hidemasa Oh
CIRCULATION 126 ( 21 ) 2012.11
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単離心筋細胞への高伸展刺激負荷のための新たな細胞保持系の確立
金子 智之, 入部 玄太郎, 貝原 恵子, 成瀬 恵治
生体医工学 50 ( 4 ) 398 - 398 2012.8
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Effects of azelnidipine on single cardiomyocyte mechanics
G. Iribe, K. Kaihara, H. Ito, K. Naruse
EUROPEAN HEART JOURNAL 32 887 - 887 2011.8
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心室筋細胞の収縮性に対するアゼルニジピンの影響
貝原恵子, 入部玄太郎, 成瀬恵治
日本生理学雑誌 73 ( 2 ) 2011
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Stretch-Sensitivity of Stretch-Activated BKCa Channels in Post-Hatch Chick Ventricular Myocytes
Gentaro Iribe, Keiji Naruse
BIOPHYSICAL JOURNAL 98 ( 3 ) 335A - 335A 2010.1
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ROLE OF STRETCH-ACTIVATED BKCA CHANNELS ON STRETCH-INDUCED ARRHYTHMIAS IN ISOLATED CHICK VENTRICLE
G. Iribe, H. Jin, K. Naruse
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY 20 S64 - S64 2009.10
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Effects of bepridil on stretch-induced arrhythmia in isolated chick ventricles
G. Iribe, H. Jin, K. Naruse
EUROPEAN HEART JOURNAL 30 32 - 32 2009.9
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孵化後のトリ心筋SAKCAチャネルの伸展感受性
入部玄太郎, JIN Honghua, 永井祐介, 貝原恵子, 成瀬恵治
日本生体医工学会大会プログラム・論文集(CD-ROM) 48th 2009
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MECHANICAL MODULATION OF CARDIAC CALCIUM HANDLING
Gentaro Iribe
JOURNAL OF PHYSIOLOGICAL SCIENCES 59 67 - 67 2009
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Modeling study of load-(in)dependency in single myocardial cell mechanics
Gentaro Iribe, Michiel Helmes, Peter Kohl
BIOPHYSICAL JOURNAL 476A - 476A 2007.1
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Dynamic force/length control of isolated cardiomyocytes
G Iribe, P Kohl
BIOPHYSICAL JOURNAL 88 ( 1 ) 120A - 120A 2005.1
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Diastolic stretch causes transient increase in sarcoplasmic reticulum Ca2+ content without concurrent rise in resting [Ca2+](i) in isolated guinea-pig ventricular myocytes
G Iribe, PJ Cooper, P Kohl
BIOPHYSICAL JOURNAL 86 ( 1 ) 136A - 136A 2004.1
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Diastolic stretch causes transient increase in sarcoplasmic reticulum Ca2+ content without concurrent rise in resting [Ca2+](i) in isolated guinea-pig ventricular myocytes
G Iribe, PJ Cooper, P Kohl
BIOPHYSICAL JOURNAL 86 ( 1 ) 136A - 136A 2004.1
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Real-time measurement of left ventricular transmural crossbridge dynamics in beating rat hearts by a synchrotron radiation system: SPring-8
J Araki, N Yagi, J Shimizu, G Iribe, K Nakamura, K Hashimoto, H Okuyama, K Tsujioka, F Kajiya
CIRCULATION 106 ( 19 ) 95 - 95 2002.11
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Functional role of capillaries in reactive hyperemia by direct observation with a pencil-lens intravital videomicroscope
T Kiyooka, O Hiramatsu, F Shigeto, T Kajita, H Nakamoto, T Yamamoto, T Yada, Y Ogasawara, H Minami, G Iribe, J Shimizu, J Araki, F Kajiya
CIRCULATION 106 ( 19 ) 278 - 278 2002.11
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EFFECTS OF HEART RATE ON EXCITATION-CONTRACTION COUPLING ENERGETICS IN CANINE LEFT VENTRICLE
Kiyooka Takahiko, Iribe Gentaro, Shimizu Juichiro, Ohsima Yu, Doi Yumiko, Hujinaka Waso, Imaoka Takeshi, Araki Junichi, Kajiya Fumihiko, Matsubara Hiromi, Ohe Toru, Suga Hiroyuki
Circulation journal : official journal of the Japanese Circulation Society 66 441 - 441 2002.3
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Validity of transeient Ees compared with stable Ees
Imaoka Takeshi, Araki Junichi, Shimizu Juichiro, Iribe Gentaro, Kiyooka Takahiko, Fujinaka Waso, Ohshima Yu, Doi Yumiko, Kajiya Fumihiko, Matsubara Hiromi, Ooe Tooru, Suga Hiroyuki
Circulation journal : official journal of the Japanese Circulation Society 66 496 - 496 2002.3
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Emergent mechanisms of sustained and transient cardiac alternans.
NAKAO YOSHIAKI, NOMURA TAISHIN, SATO SHUNSUKE, IRIBE GENTARO, ARAKI JUN'ICHI, KAJIYA FUMIHIKO
電子情報通信学会技術研究報告 101 ( 734(MBE2001 182-197) ) 65-70 - 70 2002.3
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A new myocardial calcium dynamics model in excitation-contraction coupling
G Iribe, F Kajiya, J Araki, H Suga
FASEB JOURNAL 15 ( 4 ) A490 - A490 2001.3
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Probability function for cardiac contraction
J Araki, G Iribe, J Shimizu, S Mohri, F Kajiya
FASEB JOURNAL 15 ( 4 ) A490 - A490 2001.3
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Olprinone, but not milrinone, improves hepatosplanchnic circulation after cardiac surgery.
G Iribe, H Yamada, A Matsunaga, N Yoshimura
ANESTHESIA AND ANALGESIA 86 ( 2S ) U60 - U60 1998.2
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Effect of prostaglandin E1 and nitroglycerine on portal venous flow during extracorporeal circulation: Noninvasive assessment by transesophageal echography
G Iribe, Y Ohnishi, Y Hayashi, M Kuro
ANESTHESIOLOGY 85 ( 3A ) A95 - A95 1996.9
Presentations
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心筋のカルシウム-筋線維相互作用モデルによる左室圧容量依存性の解析
第40回日本エム・イー学会大会 2001
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Application of mechanobiological engineering to regenerative and reproductive medicine
第56回日本生体医工学会大会 2017
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TRPC3 participates in the angiotensin II type 1 receptor-dependent slow force response to stretch in mouse cardiomyocytes
7th International Workshop on Cardiac Mechano-Electric Coupling and Arrhythmia 2016
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Effects of azelnidipine on single cardiomyocyte mechanics
ヨーロッパ心臓病学会2011 2011
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Effects of axial stretch on calcium handling in sarcoplasmic reticulum and mitochondria
The 5th Shanghai International Conference on Biophysics and Molecular biology 2011
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Mechano-electric interaction and arrhythmia
第91回日本生理学会大会 2014
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Physiological implications of mechanosensitive responses in cardiomyocyte organelles
International Symposium on Mechanobiology 2014
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Localization of TRPC3 channels estimated by in-silico and cellular functional experiments
Experimental and Computational Biomedicine 2016
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TRPC3 participates in the angiotensin II type 1 receptor-dependent slow force response to stretch in mouse cardiomyocytes
The 45th European Muscle Conference 2016
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Activation of TRPC3 and TRPC6 initiated by AT1 receptor regulates the slow force response in mouse ventricular myocytes.
International Symposium on Mechanobiology 2014
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Effects of axial stretch on mitochondrial reactive oxygen species in cardiac myocytes
第53回日本生体医工学会大会 2014
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Influence of stretch on transmural gradient in mechanical properties of single ventricular cells
Physiological Society meeting 2015 2015
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Role of TRPC3 in a Slow Force Response to Stretch on Mice Cardiomyocytes
第8回アジア・オセアニア生理学会連合(FAOPS)2015年大会 2015
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Mechanical modulation of cardiac calcium handling
第36回世界生理学会 2009
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Mechano-electric interaction via calcium handling
第36回世界生理学会サテライトシンポジウム＃８ 2009
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Effects of bepridil on stretch-induced arrhythmia in isolated chick ventricles
ヨーロッパ心臓病学会2009 2009
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Role of stretch-activated BKca channels on stretch-induced arrhythmias in isolated chick ventricle
11th International Workshop on Cardiac Arrhythmias 2009
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ソフトリソグラフィーを中核技術とした単一細胞の機械刺激受容機構の解明
第26回日本ロボット学会学術講演会 2008
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心室伸展刺激誘発性不整脈におけるSAKCAチャネルの役割
第31回日本生体医工学会中国四国支部大会 2008
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シリコン樹脂性平面パッチクランプ測定系の開発
第31回日本生体医工学会中国四国支部大会 2008
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孵化後のトリ心筋SAKCAチャネルの伸展感受性
第48回日本生体医工学会大会 2009
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機械受容大コンダクタンスCa2+活性化K+（SAKCA）チャネルが興奮収縮連関に及ぼす影響 ＝シミュレーションによる検討＝
第47回日本生体医工学会大会 2008
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New Insight into Acute Stretch Effects on Cardiac Calcium Handling
European Society of Cardiology Congress 2008 2008
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Single cell mechanics under dynamically changing mechanical load
International Symposium on Biological and Physiological Engineering 2008
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心筋短縮中のミオシンヘッドの挙動
第７９回日本生理学会大会 2002
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Time-resolved X-ray diffraction study in rat cardiac muscle
第７９回日本生理学会大会 2002
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カーボンファイバーを使った単離心筋細胞の生理的機械負荷の再現とその力学およびカルシウム動態応答
第46回日本生体医工学会大会 2007
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Mechanics and Ca handling study in mechanically loaded single cell using carbon fibre technique.
BBSRC Japan Partnering Programme 2007-2011 --Cardiac Electro-Mechanical Function: Cell-Oran Cross-Talk Revealed via Integration of Experiments and Models 2007
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弁疾患重症度と至適心拍数管理＝シミュレーションによる検討＝
日本麻酔学会第４８回大会 2001
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興奮収縮連関の新しいカルシウム動態モデル
第40回日本ME学会大会 2001
Awards
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Sevier Poster Award
2005
Research Projects
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心筋機械感受性制御におけるROSシグナリングの役割とその心不全治療への展開
Grant number：21K12640 2021.4 - 2024.3
日本学術振興会 科学研究費助成事業 基盤研究(C)
入部 玄太郎, 山口 陽平, 貝原 恵子, 金子 智之
Grant amount：\4,290,000 （ Direct Cost: \3,300,000 、 Indirect Cost：\990,000 ）
本年度は、単離心筋細胞で観察される伸展誘発性ROS産生増加による筋小胞体カルシウムハンドリングの修飾がどのように心筋メカニクスに影響しているかを、野生型およびNOX2ノックアウト（KO）マウス心筋細胞の伸展誘発性カルシウムトランジェント変化、心筋細胞長さ張力関係による力学解析から検討した。
その結果、心筋細胞の収縮性の指標となる収縮期末長さ張力関係の傾き（最大弾性率）は野生型に比べてNOX2KOマウスでは有意に低下していた。伸展によるカルシウムトランジェント波形は野生型のマウス心筋細胞では変化が無かったが、NOX2KOマウス心筋細胞においては細胞内カルシウム濃度の上昇率が最大に達するまでの時間が伸展によって有意に遅延することが明らかとなった。
NOX2はリアノジン受容体を刺激することが知られているが、このカルシウムトランジェントの変化がNOX2による伸展誘発性ROS産生の有無によって説明ができるのか、また、この変化がNOX2KOマウス心筋の収縮性低下を説明できるのかをコンピュータシミュレーションによって検討した。心筋細胞数理モデルとしてIribe-Kohl-Nobleモデルを用いた。このリアノジン受容体モデルの活性化レートを上げ、同時にリアノジン受容体からのカルシウムリーク率を上げることでNOX2がリアノジン受容体に及ぼす影響を再現した。前者はカルシウムトランジェントの立ち上がりをやや早め、ピークを上昇させるが、後者はピークを減弱させる効果があり、結果としてピークは変わらず立ち上がりの早いトランジェント波形となった。また、前者は発生張力を増加させる効果があり、後者は発生張力をわずかに減少させる効果があるがその効果は弱く、結果的に収縮力は増加することとなり、細胞実験の結果を再現することができた。 -
Force-Length Relationによる単離ヒト心筋細胞の機能評価
Grant number：21K08866 2021.4 - 2024.3
日本学術振興会 科学研究費助成事業 基盤研究(C)
小松 弘明, 貝原 恵子, 入部 玄太郎, 小谷 恭弘
Grant amount：\4,160,000 （ Direct Cost: \3,200,000 、 Indirect Cost：\960,000 ）
ラットやマウスにおける心筋細胞の単離操作やそれによって得られた単離心筋細胞の力学実験は安定した成績を収めている。我々は先行研究でForce-Length Control Systemによって単一細胞に分解したマウス心筋細胞を直接的に伸展収縮させることでin vitroで負荷非依存性の心機能評価を行うことを可能とした。我々が多く携わる先天性心疾患患者における余剰心筋にこの技術を応用し、細胞レベルで収縮力を解析する実験を行っている。2021年度においてマウスによる心筋細胞の単離・伸展実験の手技の習得と並行し、ヒト心筋細胞での単離・伸展実験を開始した。これまでで5例のヒト心筋細胞を用いた実験を行い、ヒト心筋細胞の単離は行うことができた。今後、ヒト単離心筋細胞を用いた伸展実験を行う予定である。
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新規メカニカル負荷装置の開発を通した次世代メカノメディスンへの挑戦
Grant number：21H04960 2021.4 - 2024.3
日本学術振興会 科学研究費助成事業 基盤研究(A)
成瀬 恵治, 西山 雅祥, 高橋 賢, 片野坂 友紀, 森松 賢順, 入部 玄太郎
Grant amount：\43,290,000 （ Direct Cost: \33,300,000 、 Indirect Cost：\9,990,000 ）
1. ストレッチ・静水圧負荷装置の開発：バルク型および顕微鏡型の開発を行った。基本設計は終了しており、微調整を行っている。
2. 軟骨に対するマルチメカニカルストレスへの応答解析：高圧受容応答メカニズムの解明を最終目的とし、高静水圧刺激による細胞及び、細胞内分子の挙動計測を実施した。定常圧力20 MPa以上の圧力を1時間負荷した際、シグナル伝達物質に関わるSmad 3タンパク質の細胞質から細胞核内への核移行が観察された。この圧力に依存したSmad 3の核内移行過程には、TGF-β receptor の活性化やImportin bとの結合が必要であることが分かり、高静水圧に依存したSmad 3核内移行メカニズムの提案が可能となった。
3. 心筋細胞に対するマルチメカニカルストレスへの応答解析：循環器における機械感受性イオンチャネルTRPV2の役割を、組織特異的TRPV2ノックアウトマウスを用いて、明らかにしてきた。その過程で、TRPV2は、心臓への圧負荷依存的肥大や心不全、血管の筋原性緊張や肥厚などに大きく関与する因子であることが明らかとなった。
4. 剪断応力・ストレッチチャンバーでのiPS心筋細胞3次元培養：剪断応力とストレッチの同時刺激が可能な臓器チップを用い、血管内皮細胞を播種した状態で、血管収縮の調節因子である一酸化窒素(NO)のライブイメージングを行った。その結果、ストレッチ刺激および圧力刺激に応じたNOの放出が確認された。
5. 心筋細胞標本の機能評価：心筋細胞のメカニカルストレスとそれに対する応答及び応答伝播の相互関係を観察するため、細胞を直列に配列させる培養法の開発を行った。フォトエッチング技術により描画した直線状パターンを鋳型としたPDMS製のマイクロ流路を作製し、これをイオンボンバーダーで親水処理した。これを用いてマウス幼若心筋細胞を播種することで、細胞を一次元的に配向させた状態で培養することに成功した。 -
Investigation of NOX4-mediated mechanotransduction in mechanically-induced cardiac failure
Grant number：20K12598 2020.4 - 2023.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Grant amount：\4,290,000 （ Direct Cost: \3,300,000 、 Indirect Cost：\990,000 ）
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Physiological and pathophysiological role of NOX4 in cardiac mechano-transduction
Grant number：17K01359 2017.4 - 2020.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Kaihara Keiko
Grant amount：\4,550,000 （ Direct Cost: \3,500,000 、 Indirect Cost：\1,050,000 ）
Reactive oxygen species (ROS) synthesized by NADPH oxidase (NOX) in vivo is a very important physiologically active substance. Although, myocardial stretch-induced ROS production via NOX2 modulates Ca2+ handling and cellular contractility, behavior of NOX4 is unknown. In the present study, we investigated the physiological and pathophysiological role of NOX4 in cardiac mechano-transduction.
Ventricular cells isolated were subjected to 5-10% axial stretch with the cardiomyocyte stretch system, were measured ROS production, Ca2+ spark rate, mitochondrial membrane potential and cellular contractility. Cellular contractility and ROS production were significantly suppressed in NOX2 KO and NOX4 KO, but Ca2+ spark rate was suppressed only in NOX2 KO. The results suggest that role of NOX4 during stretch is different from that of NOX2. On the other hand, from the results of TAC model mice, there was an effect of NOX4 on overload, but details could not be clarified. -
Multi-level analysis of ischemic heart disease pathology based on heterogeneity in mechano-electric coupling
Grant number：16K12878 2016.4 - 2018.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
Iribe Gentaro
Grant amount：\3,640,000 （ Direct Cost: \2,800,000 、 Indirect Cost：\840,000 ）
Myocardial cellular function is different between endocardial and epicardial cells. It is not clear how ischemic condition affects this transmural heterogeneity. In the present study, we isolate the cells from epicardium and endocardium to compare the response of their mechanical properties to stretch. We found that ischemic condition reduces the transmural heterogeneity in the response to stretch. The present findings may provide new insight into pathophysiology of ischemic heart disease.
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Mechanomedicine: Application of mechanobiological engineering to regenerative and reproductive medicine
Grant number：26220203 2014.5 - 2019.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (S)
NARUSE Keiji
Grant amount：\201,760,000 （ Direct Cost: \155,200,000 、 Indirect Cost：\46,560,000 ）
We induced differentiation of human induced pluripotent stem cells into spontaneously beating cardiomyocytes. We elucidated that the cardiac differentiation is facilitated by cyclic stretch stimulus and co-culture with human fibroblasts. It is suggested that stretch stimulus to cardiac stem cells induces release of paracrine factors, thereby increase cardiac contractility. With regard to autotransplantation of cardiac stem cells in pediatric dilated cardiomyopathy, we conducted the TICAP-DCM phase I trial and performed surgery for three patients successfully.
We also studied the effect of mechanical stimulus on gene expression of fertilized eggs in mice and found that the expression of genes related to embryo development and cell death was altered in response to mechanical stimulus. In addition, we successfully developed a high-quality silicone resin incubation chamber for human fertilized eggs. Furthermore, we found that hydrostatic pressure activates sperm activity. -
Role of reactive oxygen species in physiology and pathophysiology of cardiac biomechanics
Grant number：26282121 2014.4 - 2017.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
Iribe Gentaro, NISHIDA Motohiro, NARUSE Keiji
Grant amount：\16,640,000 （ Direct Cost: \12,800,000 、 Indirect Cost：\3,840,000 ）
Chronic mechanical load to myocardium due to hypertension or cardiac valve diseases leads to the heart failure. Any substances that mediate such response look “evil”, though, they also have physiological roles. Therefore, it is important to understand their physiological and beneficial roles, otherwise any attempts aimed to eliminate such “evil” substances would have side effects by eliminating their physiologically required roles. In the present study, roles of reactive oxygen species (ROS), which has been regarded as an “evil” substance, in physiological and pathological response to myocardial mechanical load was studied, and its role in linking cardiac physiology and pathophysiology was demonstrated. The present results may be useful for the development in safe methods for the treatment and/or prevention of heart failure without side effects.
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心疾患治療に向けた革新的次世代メカノ組織工学・再生医療の創生
Grant number：26242042 2014.4 - 2015.3
日本学術振興会 科学研究費助成事業 基盤研究(A)
成瀬 恵治, 王 英正, 高橋 賢, 入部 玄太郎
Grant amount：\23,270,000 （ Direct Cost: \17,900,000 、 Indirect Cost：\5,370,000 ）
心臓再生医療において、力学的・機械的刺激（メカニカルストレス）を用いた新しい技術を開発するために研究活動を行った。まず、心臓機能障害の動物モデルを作出するためにin vivoでECGを記録しつつラット冠状動脈左前下行枝(LAD)を結紮する実験を行った。組織学的解析の結果、LAD支配領域に心筋壊死による梗塞巣が形成されていることが確認された。計画段階において、心機能障害のモデルとして心筋梗塞モデルと右心不全モデルの作出を想定していたが、心筋梗塞モデルの作出は達成された。
細胞培養による移植細胞の作出実験に関しては、3次元培養用の培養装置の開発を行い、これを用いた細胞培養を開始した。新生児ラットの単離心筋細胞およびラット心筋細胞株を用いた実験により、ゲルを足場にして細胞が3次元的に生育あるいは増殖することを確認した。この成果により、ずり応力およびストレッチによる機械的刺激を細胞に負荷する環境が確立された。
またOxford大学客員教授のPeter Kohlを招聘し、メカニカルストレスによる心臓再生医療の開発に関しディスカッションを行った。さらにメカノバイオロジーの世界的な権威が集う国際学会International Symposium on Mechanobiology 2014に研究者を参加させ、関連研究領域の情報収集を行った。また3次元プリンタのワークショップにも研究者を参加させ、細胞培養用の培養器開発の実務的知見を取得させた。
本研究の内容を包括する基盤研究(S)「メカノメディスン：メカノ医工学を駆使した再生医療・生殖医療への展開」の交付決定に伴い、本研究課題を終了しこれに引き継ぐこととした。 -
role of mechanosensitive response of organelle in dynamic biomechanics of cardiomyocytes
Grant number：23300167 2011.4 - 2014.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
IRIBE Gentaro, WAKIMOTO Shuichi, NARUSE Keiji
Grant amount：\18,720,000 （ Direct Cost: \14,400,000 、 Indirect Cost：\4,320,000 ）
Calcium spark is diastolic spontaneous calcium releasing event from ryanodine receptors (RyR) on sarcoplasmic reticulum. We have previously reported that myocardial stretch increases calcium spark rate. It has been regarded that stretch-induced increase in reactive oxygen species (ROS) production from NADPH oxidase stimulates RyR to cause the phenomenon. However, the present study revealed that stretch-induced increase in ROS production is derived from mitochondria.
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Integrative study on arrhythmogenicity associated with adaptive and pathological remodeling of stressed hearts.
Grant number：22136008 2010.4 - 2015.3
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
INOUE Ryuji, IRIBE Gentaro, NAKAYA Michio, MATSUOKA Satoshi
Grant amount：\85,540,000 （ Direct Cost: \65,800,000 、 Indirect Cost：\19,740,000 ）
The present study aimed at exploring novel pathogenic mechanisms underlying abnormal excitability and arrhythmic changes in stressed hearts. For this purpose, we focused on stress-responsive Ca2+/Na+ channel molecules transient receptor potential (TRP) proteins, and investigated their pathological significance by combining both experimental and theoretical approaches. The results clearly indicate that post-remodeling upregulation as well as small differences in PIP2 sensitivity among highly homologous isoforms and arrhythmic mutations could account for part of their notably different functionalities, leading to enhanced risk of arrhythmias and abnormal excitability. This integrative approaches of experiments and numerical model-based simulations may provide a useful framework to design/develop new anti-arrhythmic drugs targeting TRP channels and simultaneously facilitate our understanding about an otherwise elusive complexity of cardiac excitation/propagation and its disorders.
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Elucidation of Biological Adaptation and Remodeling Mechanisms to Mechanical Stress Based on the Development of Novel Micro-Electro-Mechanical Systems (MEMS) technology
Grant number：22240056 2010 - 2012
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)
NARUSE Keiji, MOHRI Satoshi, NAKAMURA Kazufumi, TAKEI Kohji, YAMADA Hiroshi, IRIBE Gentaro, KATANOSAKA Yuki
Grant amount：\50,570,000 （ Direct Cost: \38,900,000 、 Indirect Cost：\11,670,000 ）
Physical and mechanical stimuli such as gravity, extension, and shearing stress are generated throughout a living body. It has been gradually revealed that these stimuli, which are transmitted via the mechanotransduction mechanisms of cells, are not simply detrimental stresses for living organisms, but rather are biological information essential to developmental processes and functional adaptation of organs. In this project, on the basis of the development of original loading systems for mechanical stress to cells and tissues, the cellular adaptive responses to the mechanical stimuli and their transduction mechanisms in a variety of mechanosensitive tissues are to be examined. Thus, the project aims toelucidate the molecular mechanisms and roles of mechanotransduction system, which is utilized as a basis of many physiological events. It can also contribute to develop therapeutic approach to cancer invasion, cardiac hypertrophy, and regeneration of neuronal circuit.
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Role of mechanical load in human myocardial excitation contraction coupling
Grant number：20300159 2008 - 2010
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
IRIBE Gentarou, NARUSE Keiji, MOURI Satoshi, KATANOSAKA Yuki, SANO Shunji, OOSHIMA Yuu
Grant amount：\16,900,000 （ Direct Cost: \13,000,000 、 Indirect Cost：\3,900,000 ）
The normal heartbeat is the results of complex interactions of individual cardiomyocytes in the heart. Any mechanical disturbance in their interaction could be the risk of heart rhythm disturbances. In the present study, we revealed the underlying mechanisms that cause mechanically-induced arrhythmic beat by investigating mechanically-induced influx and efflux of ions via mechano-sensitive channels.
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単離心筋機械負荷操作を用いた心臓の機械電気相互作用の統合生理研究
Grant number：20034038 2008 - 2009
日本学術振興会 科学研究費助成事業 特定領域研究
入部 玄太郎
Grant amount：\7,600,000 （ Direct Cost: \7,600,000 ）
21年度前半は前年度後半に引き続き単離心筋細胞レベルの伸展実験と臓器レベルの機械電気相互作用としてトリ心臓における機械刺激誘発性不整脈実験をおこなった。これらの実験から伸展刺激誘発性不整脈に対するSAKCAチャネル(伸展感受性BKチャネル)や機械受容非選択的陽イオンチャネル(nSAC)などの関与が明らかとなったが、21年度後半はそれらの機械電気相互作用実験結果を心筋細胞数理モデルに統合するためのシミュレーション実験を行った。心筋細胞モデルとしては、Iribe-Kohl-Nobleモデルの電気生理・カルシウム動態モデルを用いた。伸展刺激によるnSACを介したナトリウム流入電流は背景ナトリウム電流のコンダクタンスを変化させることにより再現した。伸展刺激によるSAKCAチャネルを介したカリウム流出電流はMoczydlowskiらのBKチャネルモデルのコンダクタンスを変化させることにより再現した。機械刺激誘発性不整脈はnSACの活性化による脱分極によって誘発されるとされているが、このメカニズムは再現された。また、我々の実験結果に基づき、筋小胞体からのカルシウム放出を機械刺激に伴って増加させたところ、このメカニズムによっても不整脈が誘発されることが示唆された。背景K電流に伸展感受性を持たせた場合は機械刺激誘発性不整脈を抑制したが、我々の実験結果とは異なりSAKCA電流は機械刺激誘発性不整脈を抑制しなかった。現在の所、nSACの分子実態は不明でその数理モデルも確立されていない。背景電流のコンダクタンスを変化させるのみの単純なnSACモデルでは実験結果を完全には再現できなかったものと思われ、さらにnSACの電気生理的特徴を詳細に解明していく必要がある。
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The role of mechanosensor on cardiovascular disease.
Grant number：19200037 2007 - 2009
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)
NARUSE Keiji, MORI Satoshi, MATSUI Hideki, TOMIZAWA Kazuhito, KATANOSAKA Yuki, IRIBE Gentaro, NAKAMURA Kazufumi, KUSANO Kengo, OHE Tohru
Grant amount：\49,400,000 （ Direct Cost: \38,000,000 、 Indirect Cost：\11,400,000 ）
In order to elucidate the in vivo mechanotransduction system, it is essential to conduct molecular cell physiological analysis targeting mechanosensitive channel molecules, as well as physiological assessment using knockout mice. In this study, we will examine whether or not hemodynamic loads such as hypertension can cause such dysfunction of the mechanosensitive channel, and explore the roles of the mechanosensor in relation to the formation of hypertrophy and progression of heart failure. The elucidation of the molecular pathway involved in the exacerbation of heart failure will enable us to sift through novel treatment target molecules and treatment research subjects in line with the actual clinical settings.
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Application of Soft Lithography to Mechanobiology
Grant number：17076006 2005 - 2009
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas
NARUSE Keiji, TAKAI Akira, MIYAZU Motoi, MOHRI Satoshi, KATANOSAKA Yuki, IRIBE Gentaro
Grant amount：\101,500,000 （ Direct Cost: \101,500,000 ）
In this research project, we focused on mechanosensitive mechanism of mammalian from molecular to individual level. We constructed analysis methods of mechanical and medicinal stimuli using softlithography to construct features measured on the micrometer to nanometer scale, and then employed it into stimuli-response analysis. High-speed atomic force microscope was applied to observe molecular dynamics in aqueous environment with high spatiotemporal resolution, and we elucidated molecular dynamics of the mechanosensitive molecules.
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心筋クロスブリッジ動態ナノメカニクスが心臓ポンプ機能に及ぼす影響
Grant number：14770315 2002
日本学術振興会 科学研究費助成事業 若手研究(B)
入部 玄太郎
Grant amount：\2,100,000 （ Direct Cost: \2,100,000 ）
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Analysis of coronary microcirculation and myocardial crossbridge dynamic using SPring-8 synchrotron facility
Grant number：13854030 2001 - 2004
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (S)
KAJIYA Fumihiko, SUGA Hiroyuki, YAGI Naoto, OHE Toru, SHIMIZU Jyuichiro, MOHRI Satoshi
Grant amount：\91,000,000 （ Direct Cost: \70,000,000 、 Indirect Cost：\21,000,000 ）
Global dynamics of coronary circulation and cardiac contraction have been well documented in cardiology and circulatory physiology. Recently, transmural, i.e., from epicardial to endocardial heterogeneities have been getting more important for better understanding of the cardiac pathophysiology. Thus the objective of this study was to reveal the detailed transmural characteristics of the myocardial crossbridge dynamics and the coronary micro-circulation.
Firstly, we found that the diastolic predominant flow pattern was common throughout myocardial layers. During systolic phase, significant systolic reverse flow was observed in subendocardial arterioles, whereas a remarkable forward flow was observed in subepicardial arterioles. Intramural pressure gradient and myocardial stiffness (elastance) cause these transmural dissociations in systolic flow direction. We also found the vessel size dependent coronary vascular regulation system, and spatial and temporal myocardial flow heterogeneity using the SPring-8, custom-made intravital CCD microscopes, and molecular isotope tracers.
Secondly, we revealed the transmural difference of crossbridge dynamics using the SPring-8. During contraction phase, subepicardial and midcardial crossbridge dynamics were harmonized well each other and synchronized with the left ventricular pressure development. However the crossbridge of deeper myocardium decayed earlier than that of subepicardium during relaxation phase. Earlier relaxation in the myocardium in deeper regions seemed to be beneficial for diastolic blood inflow into deeper myocardium.
We are now going to promote the "Physiome" as the quantitative and integrated description of the functional behavior of the physiological state. We believe that the present studies contribute to the cardiovascular physiome in the sense that it clarified the close coupling between coronary microcirculation and actin-myosin macromolecular dynamics. (256/300 words) -
病態モデル小動物における腎糸球体微小循環可視化法の開発と病態生理学的解析
Grant number：13878185 2001 - 2002
日本学術振興会 科学研究費助成事業 萌芽研究
梶谷 文彦, 清水 壽一郎, 荒木 淳一, 清野 佳紀, 小笠原 康夫, 毛利 聡, 入部 玄太郎
Grant amount：\2,100,000 （ Direct Cost: \2,100,000 ）
ペンシルレンズ型のCCD生体顕微鏡(分解能0.86μm、約800X)を用いて病的ラット(虚血・糖尿病・高血圧)の腎糸球体微小循環を可視化し、新たに開発した糸球体内血流速度分布計測のために画像処理ソフトを用いて各病態における微小循環の変化について解明することができた。
腎動脈の閉塞・開放による虚血再灌流モデルでは、管周囲および糸球体での微小循環を観察した。(Am J Physiol Renal Physiol.282(6):F1150-5,2002)両部位において閉塞前では血流は順行性であったが、虚血再灌流後では一過性の血流停止と逆行性血流を認めた。その後の経過では管周囲よりも糸球体の微小循環のほうが早く正常状態へ復帰した。これらの結果より腎皮質表面では虚血再灌流の早期から血管障害が生じており、管周囲の微小循環には糸球体周囲と比較し、より大きな影響があることが示された。
糖尿病、高血圧モデルの実験では、それぞれstreptoyotocin投与ラット、自然発症高血圧ラットを使用した。(Am J Physiol Renal Physiol.281(3):F571-7,2001)輸入細動脈、輸出細動脈を同時に観察し、対照群に比べて自然発症高血圧ラットでは輸入細動脈径が縮小し、糖尿病では逆に拡大していることがわかった。カルシウム拮抗薬であるBarnidipineの投与では高血圧腎では輸入細動脈の拡張が著明で、糖尿病腎では輸出細動脈の拡張が優位に観察された。血管径比(輸入細動脈径/輸出細動脈径)はそれぞれ有意に増加・減少していた。
本研究により、多様な病態における腎微小循環ダイナミクスの変化について評価することが出来た。これら一連の結果は糸球体病態生理の更なる理解に繋がると考える。 -
複合化原子間力顕微鏡を応用した単離心筋細胞骨格化に伴う力学と代謝特性の解析
Grant number：13558113 2001
日本学術振興会 科学研究費助成事業 基盤研究(B)
梶谷 文彦, 入部 玄太郎, 清水 壽一郎, 荒木 淳一, 片岡 則之, 小笠原 康夫
Grant amount：\8,500,000 （ Direct Cost: \8,500,000 ）
原子間力顕微鏡をもちいて細胞の弾性率を求める研究はこれまでにも行われているが、動的な筋細胞とは異なる細胞種が対象であった。特に心筋細胞に対する解析は皆無に等しい。その原因は非常に繊細なセンサーである原子間力顕微鏡のカンチレバーの感度に対し、ダイナミックに動く心筋細胞の挙動がノイズとなり、シグナルノイズレシオ(S/N比)が非常に低くなることが原因であると思われる。我々のグループではこの問題を解決するため、心筋の筋長を制御する機構を組み込むことにより任意の筋長での等尺性収縮および制御された短縮様式で測定できる系を立ち上げている段階である。一方、筋細胞に対する原子間力顕微鏡を用いた弾性率変化の解析の妥当性を確認するため、心筋より静的な収縮弛緩をみせる血管平滑筋細胞を用いた測定を行っている。結果は我々の予想したとおり、血管収縮物質であるノルアドレナリンおよびアンジオテンシンIIで処理をした場合には平滑筋細胞の弾性率は増加し、血管弛緩物質であるプロスタサイクリン,NOの投与時には逆に弾性率の低下が確認できた(日本循環器学会、日本ME学会、2002)。したがって当初予定していた心筋細胞の心不全時における細胞骨格の変化は筋弛緩期の、収縮力低下などを引き起こす収縮蛋白の異常は収縮時の弾性率を測定することによりそれぞれ解析できるものと思われる。また、血管平滑筋に対する解析を発展させ肺高血圧症患者由来の平滑筋細胞を用いた解析を行い病態解明の一助としたい。
(基盤(S)採択のため年度途中で辞退) -
SPring8放射光を用いた重元素ステレオ造影による心筋微小血管ダイナミクス解析
Grant number：12480269 2000 - 2001
日本学術振興会 科学研究費助成事業 基盤研究(B)
梶谷 文彦, 荒木 淳一, 松本 健志, 小笠原 康夫, 入部 玄太郎, 清水 壽一郎, 梅谷 啓二
Grant amount：\13,500,000 （ Direct Cost: \13,500,000 ）
冠動脈および冠静脈の血流には位相の違いが認められ、拡張期に血液を貯留し、収縮期に貯留した血液を搾り出す挙動を示す心筋内容量血管の重要性を示唆している。このような心筋内容量血管の解剖学的、機能的な解析を目的に、拡張期および収縮期における心筋内微小血管の三次元可視化と特徴的な機能の解析を行った。ラットランゲンドルフ心標本を用い、St.Thomas液灌流により完全弛緩状態あるいは塩化バリウムにて拘縮状態としたのち造影剤を末梢まで完全に充填した。このように作成した標本を共焦点レーザースキャン顕微鏡およびSPring-8放射光を利用したX線マイクロCTにマウントし、貫壁性の毛細血管および毛細血管よりやや径の大きい微小血管の三次元構築を明らかにした。単位心筋あたりの血管容積および収縮期の血管容積減少率を求めた。まず、毛細血管の単位心筋あたり拡張期には約20%とより太い血管の10倍もの体積を持っことが明らかになった。さらに、心筋収縮時には拡張期の約30%まで毛細血管が虚脱することなく減少することが明らかになった。容積減少率も毛細血管において有意に小さく、太い血管での収縮時の容積減少は、血管自体の形態変化を伴うことも明らかになった。この結果から、心筋内毛細血管はその前後の血管より圧縮に対して抵抗しその形態・容積を維持するものである。このことは全心周期において毛細血管床から心筋へ酸素供給が可能であることを示す。また、毛細血管前後血管め血管抵抗の変動は、収縮期に毛細血管が虚脱しないように作用している可能性もあると考えられる。(基盤(S)採択のため年度途中で辞退)
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EVAUATION OF CROSS-SECTIONAL AREA OF CORONARY ARTERIES BY CONDUCTANCE CATHETER : TOWORD ITS APPLICATION TO PTCA
Grant number：12680832 2000 - 2001
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
ARAKI Junichl, IRIBE Gentaro, SHIMIZU Juichiro, KAJIYA Fumihiko, ITO Haruo
Grant amount：\3,600,000 （ Direct Cost: \3,600,000 ）
Objectives
The purpose of this study was to evaluate the feasibility of the conductance catheter (CC) method in measuring cross-sectional area (CSA) of small vessels like human coronary arteries.
Methods
Lumen CSA (A) of phantom tubes (2-10 mm in diameter) and excised canine arteries (n = 10, 2.3-4.5 mm in diameter) were measured with 3-F CC (Acc) and intravascular ultrasound (Aus). To investigate the influence of parallel conductance in accuracy of Ace, solution with various resistivities was applied to the surrounding of the arteries (n = 4).
Results
Acc showed an excellent agreement with phantom model CSA. In the excised arteries, Acc and Aus highly correlated (R2 = 0.906) with each other. When the resistivities of the solution surrounding the vessels was changed, Acc-Aus regression lines were similar regardless of different resistivities.
Conclusions
The conductance method is feasible to measure CSA of small vessels like human coronary arteries. -
統合生理学的分析法による心臓内カルシウム無駄サイクル数の推定法
Grant number：10877006 1998 - 1999
日本学術振興会 科学研究費助成事業 萌芽的研究
菅 弘之, 入部 玄太郎, 毛利 聡, 荒木 淳一, 實金 健
Grant amount：\1,800,000 （ Direct Cost: \1,800,000 ）
正常心筋では筋小胞体でハンドリングされるカルシウムは一心拍の間に一度だけ細胞内に放出され汲み上げられるが、不全心筋の筋小胞体カルシウム放出チャンネルには漏れが生じており、一度汲み上げられたカルシウムの一部は漏出し、収縮に関与することなく同一心拍中に再度筋小胞体に汲み上げられる。この無駄サイクルをリアノジン投与による不全心モデルで検討した。これまで我々は、定常収縮中に期外収縮を人工的に挿入し、期外収縮後の収縮性増強の指数関数減衰時定数から細胞内カルシウム再循環率を算出する方法を報告した。本研究で、この時定数はリアノジン投与モデルでは減少することがわかった。これはリアノジン投与で再循環率が低下することを示している。さらにカルシウムハンドリングの経済性と再循環率の関係と、カルシウム量に対する収縮性への反応性から、収縮に関与したカルシウムに対する無駄サイクルの割合を求めることができた。リアノジン投与にて収縮性は低下するが、カルシウムハンドリングに消費される酸素量の減少は軽度であった。これは再循環率が低下、つまりエネルギー効率のよい再循環経路の割合が低下したことと、無駄サイクルが増えるためであると考えられる。本研究による結果でもこれを裏付ける結果を得ることができた。リアノジン投与前後で得られた収縮関与カルシウム量も生理学的条件下に心筋細胞内でハンドリングされるカルシウム量として過去に報告されてきた値と同様の範囲であった。これまでの研究成果により統合生理学的分析法による心臓内無駄サイクルの推定法が妥当であることが示されている。
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Assessment of the total amount of CAィイD12+ィエD1 handled in the E-C coupling by analyzing postextrasystolic potentiation and OィイD22ィエD2 consumption : Systems approach
Grant number：10558136 1998 - 1999
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
SUGA Hiroyuki, MOHRI Satoshi, ARAKI Junichi, ITOH Haruo, IRIBE Gentaro
Grant amount：\12,200,000 （ Direct Cost: \12,200,000 ）
We have found that postextrasystolic potentiation decays in transient alternans in the canine left ventricle (LV). We used for the curve fitting the following equation : y = a・exp[-(x-1)/κィイD2eィエD2] + b・exp[-(x-1)/κィイD2eィエD2]cos[(x-1)] +1, where x = beat number and y = normalized contractility (Emax) of the postextrasystolic beats. Internal CaィイD12+ィエD1 recirculation (RF) was obtained from τe, according to the definition : RF = exp(-1/κィイD2eィエD2). We combined RF the mechanoenergetic data and the two-fold difference of the stoichiometry between the SR CaィイD12+ィエD1 pump and the transsarcolemmal extrusion route.
Using this framework, we investigated the effects of intracoronary CaィイD12+ィエD1 and epinephrine (EP) and found that CaィイD12+ィエD1 increased RF but EP did not. We obtained 40-110 micromol/kg as the total amount of CaィイD12+ィエD1 handled per beat in control and enhanced contractile state.
To evaluate myocardial CaィイD12+ィエD1 handling hearts, we hypothesized that OィイD22ィエD2 wasting of CaィイD12+ィエD1 handling in the E-C coupling could be reflected by a decreased RF in ryanodine-treated hearts. intracoronary ryanodine halved LV Emax without decreasing myocardial OィイD22ィエD2 consumption for the E-C coupling. We speculated this mehcanoenergetics to manifest energy wasting of CaィイD12+ィエD1 handling due to ryanodine-induced CaィイD12+ィエD1 leakage from the SR (futile cycle). Ryanorine decreased RF from 0.6 to 0.5 on average and the futile cycle was 1.4 times the effective cycle of CaィイD12+ィエD1 handled via the SR.
Stunning also halved LV Emax and doubled OィイD22ィエD2 cost of Emax. We found stunning decreased RF from 0.63 to 0.43 on average and caused a considerable shift of the relation between futile cycle and CaィイD12+ィエD1 reactivity in an energy-wasteful direction. These results reasonably accounted for the doubled OィイD22ィエD2 cost of Emax in stunning. Thus, we have validated the usefulness of our integrative analysis method to evaluate myocardial CaィイD12+ィエD1 handling in beating whole hearts. (297 words) -
Macro-micro correspondence in mechanoenagetics of failing hearts
Grant number：09470009 1997 - 1999
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
SUGA Hiroyuki, IRIBE Gentaro, MOHRI Satoshi, ARAKI Junichi
Grant amount：\5,900,000 （ Direct Cost: \5,900,000 ）
We have developed an organ-level systems approach to quantify total CaィイD12+ィエD1 handling in normal hearts. However, its direct application to failing hearts, where futile CaィイD12+ィエD1 cycling via the CaィイD12+ィエD1-leaky sarcoplasmic reticulum (SR) required an increased CaィイD12+ィエD1 handling VoィイD22ィエD2, was not legitimate. To quantify total CaィイD12+ィエD1 handling even in such failing hearts, we calculated internal CaィイD12+ィエD1 recirculation fraction (RF) from the exponential decay component of postextrasystolic potentiation (PESP) and combined the RF with the halved left ventricular (LV) contractility (Emax) and its OィイD22ィエD2 cost.
We applied this new integrative method to three kinds of failing hearts.
1. Failing hearts after intracoronary ryanodine at nanomolar concentrations halved Emax without significantly decreasing CaィイD12+ィエD1 handling VoィイD22ィエD2. We found that ryanodine significantly decreased RF from 0.6 to 0.5 on the average. We also found that futile CaィイD12+ィエD1 cycling via the SR increased to >1 cycle/beat after ryanodine from presumably zero before ryanodine.
2. We analyzed total CaィイD12+ィエD1 handling of the LV in the mildly failing heart preparation induced by a temporary intracoronary CaィイD12+ィエD1 overloading intervention. This intervention decreased Emax by 40% and CaィイD12+ィエD1 handling VoィイD22ィエD2 by 30% without increasing the OィイD22ィエD2 cost of Emax. We found that these failing hearts had a slightly but significantly increased RF accompanied by either a slightly increased futile CaィイD12+ィエD1 cycling or a slightly decreased CaィイD12+ィエD1 reactivity of Emax, or both. Any of these three possible changes can account for the unchanged OィイD22ィエD2 cost of Emax.
3. Postischemic myocardial stunning halved Emax and doubled OィイD22ィエD2 cost of Emax. Stunning decreased RF from 0.63 to 0.43 on the average. We found a decreased total CaィイD12+ィエD1 transport and a considerable shift of the relation between futile CaィイD12+ィエD1 cycling and CaィイD12+ィエD1 reactivity in an energy-wasteful direction in the stunned heart.