title: Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure.
abstract: BACKGROUND
  Defective interdomain interaction within the ryanodine receptor (RyR2) seems to play a key role in the pathogenesis of heart failure, as shown in recent studies. In the present study we investigated the effect of oxidative stress on the interdomain interaction, its outcome in the cardiac function in heart failure, and the possibility of preventing the problem with antioxidants.
  
  
  RESULTS
  Sarcoplasmic reticulum (SR) vesicles were isolated from dog left ventricular (LV) muscle (normal or rapid ventricular pacing for 4 weeks with or without the antioxidant edaravone). In the edaravone-treated paced dogs (EV+), but not in the untreated paced dogs (EV-), normal cardiac function was restored almost completely. In the SR vesicles isolated from the EV-, oxidative stress of the RyR2 (reduction in the number of free thiols) was severe, but it was negligible in EV+. The oxidative stress of the RyR2 destabilized interdomain interactions within the RyR2 (EV-), but its effect was reversed in EV+. Abnormal Ca2+ leak through the RyR2 was found in EV- but not in EV+. The amount of the RyR2-bound FKBP12.6 was less in EV- than in normal dogs, whereas it was restored almost to a normal amount in EV+. The NO donor 3-morpholinosydnonimine (SIN-1) reproduced, in normal SR, several abnormal features seen in failing SR, such as defective interdomain interaction and abnormal Ca2+ leak. Both cell shortening and Ca2+ transients were impaired by SIN-1 in isolated normal myocytes, mimicking the pathophysiological conditions in failing myocytes. Incubation of failing myocytes with edaravone restored the normal properties.
  
  
  CONCLUSIONS
  During the development of heart failure, edaravone ameliorated the defective interdomain interaction of the RyR2. This prevented Ca2+ leak and LV remodeling, leading to an improvement of cardiac function and an attenuation of LV remodeling.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medical Bioregulation, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan. yanoma@yamaguchi-u.ac.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yano
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okuda
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tateishi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Noma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Doi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ikemoto
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D000077553:Edaravone; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D006352:Heart Ventricles; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000975:Antioxidants; D020030:Nitric Oxide Donors; D019837:Ryanodine Receptor Calcium Release Channel; D022061:Tacrolimus Binding Protein 1A; D000077553:Edaravone; D002118:Calcium; D000983:Antipyrine