New molecular targeting therapy for regression of cardiac hypertrophy by inhibiting abnormal Ca2+ leak through RyR2 in hypertrophic cardiomyopathy

• Project/Area Number: 26670404
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YANO Masafumi 山口大学, 医学(系)研究科(研究院), 教授 (90294628)
• Co-Investigator(Kenkyū-buntansha): OKUDA Shinichi 山口大学, 大学院医学系研究科, 助教 (90530212)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肥大型心筋症 / リアノジン受容体 / カルシウムリーク / カルシウムハンドリング

Outline of Final Research Achievements

Hypertrophic cardiomyopathy(HCM) is a myocardial disorder characterized by idiopathic hypertrophy of the left ventricule. In familial HCM patients, it is the cause of sudden death by lethal arrhythmia in young age and the cause of heart failure disability at diastolic phase of HCM. However, medical approach of the regression of hypertrophy remains elusive. Here, we hypothesized that diastolic Ca2+ leak through ryanodine receptor (RyR2) is one of the important factor for triggering abnormal hypertrophy in HCM. To verify this hypothesis, we investigated the pathogenic role of Ca2+ leak through RyR2 in transgenic mouse (TG) model of familial HCM-related cardiac troponin T mutation. Diastolic Ca2+ leak through defective RyR2 caused by CaMKII activation was seen in TG cardiomyocytes and RyR2 stabilizer, dantrolene inhibited Ca2+ leak in TG. These results suggest that inhibiting Ca2+ leak by RyR2 stabilization might play a role for the regression of abnormal hypertrophy in HCM.

Research Products

• [Journal Article] An oxidative stress biomarker, urinary 8-hydroxy-2'-deoxyguanosine, predicts cardiovascular-related death after steroid therapy for patients with active cardiac sarcoidosis. (2016)
  • Author(s): Myoren T, Kobayashi S, Oda S, Nanno T, Ishiguchi H, Murakami W, Okuda S, Okada M, Takemura G, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol Volume: 17 Pages: 206-213
  • DOI: 10.1016/j.ijcard.2016.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum. (2015)
  • Author(s): Kobayashi S, Susa T, Ishiguchi H, Myoren T, Murakami W, Kato T, Fukuda M, Hino A, Suetomi T, Ono M, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Okuda S, Doi M, Yamamoto T, Yano M
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: e0114314-e0114314
  • DOI: 10.1371/journal.pone.0114314
  • Peer Reviewed / Open Access
• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis (2015)
  • Author(s): Kobayashi S, Myoren T, Oda S, Inari M, Ishiguchi H, Murakami W, Fukuda M, Tanaka T, Okuda S, Nao T, Doi M, Yamada J, Okamura T, Hoshii Y, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol. Volume: 190 Pages: 319-328
  • DOI: 10.1016/j.ijcard.2015.04.144
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comparison of neointimal coverage and extra-stent lumen between sirolimus and everolimus-eluting stent using optical coherence tomography. (2015)
  • Author(s): Oda T, Okamura T, Yamada J, Miyagi N, Uehara H, Nao T, Tateishi H, Maeda T, Nakamura T, Shiraishi K, Nakashima T, Nishimura S, Miura T, Matsuzaki M, Yano M.
  • Journal Title: Heart Vessels Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] New quantitative method to diagnose coronary in-stent restenosis by 64-multislice computed tomography (2015)
  • Author(s): Yoshimura M, Nao T, Miura T, Okada M, Nakashima Y, Fujimura T, Okamura T, Yamada J, Matsunaga N, Matsuzaki M, Yano M.
  • Journal Title: J Cardiol Volume: 65 Issue: 1 Pages: 57-62
  • DOI: 10.1016/j.jjcc.2014.03.013
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes (2014)
  • Author(s): Fukuda M, Yamamoto T, Nishimura S, Kato T, Murakami W, Hino A, Ono M, Tateishi H, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M
  • Journal Title: Biochem Biophys Res Commun Volume: 448(1) Issue: 1 Pages: 1-7
  • DOI: 10.1016/j.bbrc.2014.03.152
  • Peer Reviewed / Open Access
• [Journal Article] Does a ripple of Ca(2+) leak develop into a rogue wave that can trigger pathological hypertrophy? (2012)
  • Author(s): Yano M, Okuda S
  • Journal Title: J Am Coll Cardiol Volume: 63(15) Issue: 15 Pages: 1580-2
  • DOI: 10.1016/j.jacc.2013.10.064
  • Peer Reviewed / Open Access
• [Presentation] Inhibition of aberrant Ca2+ release through RyR2 mediated by CaMKII and Ca2+ buffering suppresses arrhythmogenesis in troponin T-related hypertrophic cardiomyopathy (2016)
  • Author(s): Okuda S, Kato T, Sufu Y, Fukuda M, Nichimura S, Kobayashi S, Oda T, Yamamoto T, Yano M
  • Organizer: Japanese Society of Cardiology
  • Place of Presentation: 宮城県仙台市 せんだい青葉山交流会場 特設会場
  • Year and Date: 2016-03-18
• [Presentation] High Affinity CaM, but Not Normal Affinity CaM Can Prevent Arrhythmias in CPVT Which Mutation is Located at CaM-like Domain of RyR2. (2015)
  • Author(s): Nishimura S, Yamamoto T, Fukui G, Maeda T, Hino A, Suetomi T, Ono M, Mochozuki M, Oda T, Okuda S, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07
• [Presentation] Dantrolene Enhances Binding of Calmodulin to RyR2 in CPVT Which Mutation Located at Central Domain but Does Not Enhance That in CPVT With Mutation at CaM-like Domain. (2015)
  • Author(s): Nishimura S, Yamamoto T, Fukui G, Maeda T, Hino A, Suetomi T, Ono M, Mochozuki M, Oda T, Okuda S, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07
• [Presentation] Dantrolene Cannot Inhibit Aberrant Ca2+ Release and Arrhythmias Without Calmodulin in Pressure Overload Heart Failure. (2015)
  • Author(s): Fuykui G, Yamamoto T, Kato T, Maeda T, Nishimura S, Hino A, Suetomi T, Ono M, Mochizuki M, Oda T, Okuda, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07
• [Presentation] A Marked Increase in Myocardial Oxidative Stress Associated With Sympathetic Hyperactivity is Related to Transient Myocardial Dysfunction in Patients With Takotsubo Cardiomyopathy (2015)
  • Author(s): Nannno T, Kobayashi S, Oda S, Ishiguchi H, Myoren T, Miyazaki Y, Suetomi T, Ono M, Mochizuki M, Oda T, Okuda S, Yamada J, Okamura T, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07
• [Presentation] Dantrolene suppresses arrhythmogenesis by inhibition of aberrant Ca2+ release mediated by CaMKII and Ca2+ buffering in troponin T-related hypertrophic cardiomyopathy (2015)
  • Author(s): Okuda S, Fukuda M, Kato T, Nichimura S, Kobayashi S, Oda T, Yamamoto T, Yano M
  • Organizer: Japanese Society of Heart Failure
  • Place of Presentation: 大阪府大阪市 グランフロント大阪
  • Year and Date: 2015-10-22
• [Presentation] RyR2 stabilization by inhibiting aberrant Ca2+ release mediated by CaMKII signaling and Ca2+ buffering function suppresses arrhythmogenesis in Troponin T-related familial hypertrophic cardiomyopathy (2015)
  • Author(s): Okuda S, Kato T, Fukuda M, Nichimura S, Kobayashi S, Oda T, Yamamoto T, Yano M
  • Organizer: European Society of Cardiology
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
• [Presentation] RyR2 Stabilization by Inhibiting Aberrant Ca2+ Release Mediated by CaMKII Signaling Within the Increase of Ca2+ Buffering Capacity Suppress Arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2014)
  • Author(s): Okuda S,Kato T, Fukuda M, Nishimura S, Oda T, Kobayashi S, Yamamoto T, Yano M
  • Organizer: American Heart Association Scientific Meeting 2014
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2014-11-18
• [Presentation] Dissociation of Calmodulin From RyR2 Causes Diastolic Ca2+ leak and Induces Lethal Arrhythmias in Pressure-overload Heart Failure (2014)
  • Author(s): Kato T, Yamamoto T, Maeda T, Nishimura S, Murakami W, Suetomi T, Ono M, Mochizuki M, Oda T, Okuda S, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2014
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2014-11-17
• [Presentation] Stabilization of RyR2 by inhibition of CaMKII-mediated aberrant Ca2+ release may suppress arrhythmogenesis in cardiac troponin T-related familial hypertrophic cardiomyopathy (2014)
  • Author(s): Okuda S, Fukuda M, Kato T, Nishimura S, Oda T, Kobayashi S, Yamamoto T, Yano M
  • Organizer: European Society of Cardiology Scientific Meeting 2014
  • Place of Presentation: Barcelona (Spain)
  • Year and Date: 2014-09-01