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(Circulation. 2005;112:3633-3643.)
© 2005 American Heart Association, Inc.

Heart Failure

Correction of Defective Interdomain Interaction Within Ryanodine Receptor by Antioxidant Is a New Therapeutic Strategy Against Heart Failure

Masafumi Yano, MD, PhD; Shinichi Okuda, MD, PhD; Tetsuro Oda, MD; Takahiro Tokuhisa, MD; Hiroki Tateishi, MD; Mamoru Mochizuki, MD; Toshiyuki Noma, BS; Masahiro Doi, MD, PhD; Shigeki Kobayashi, MD, PhD; Takeshi Yamamoto, MD, PhD; Yasuhiro Ikeda, MD, PhD; Tomoko Ohkusa, MD, PhD; Noriaki Ikemoto, PhD; Masunori Matsuzaki, MD, PhD

From the Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan (M.Y., S.O., T. Oda, T.T., H.T., M. Mochizuki, T.N., M.D., S.K., T.Y., Y.I., T. Ohkusa, M. Matsuzaki); Boston Biomedical Research Institute, Watertown, Mass (N.I.); and Department of Neurology, Harvard Medical School, Boston, Mass (N.I.).

Correspondence to Masafumi Yano, MD, PhD, Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan. E-mail yanoma{at}yamaguchi-u.ac.jp

Received April 13, 2005; revision received September 13, 2005; accepted September 19, 2005.

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.

Methods and 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.

Key Words: calcium • free radicals • heart failure • sarcoplasmic reticulum

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