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Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload

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Yasuhiro Akazawa, Manabu Taneike, Hiromichi Ueda, Rika Kitazume-Taneike, Tomokazu Murakawa, Ryuta Sugihara, Hiroki Yorifuji, Hiroki Nishida, Kentaro Mine, Ayana Hioki, Shigemiki Omiya, Hiroyuki Nakayama, Osamu Yamaguchi, Tamotsu Yoshimori, Yasushi Sakata, Kinya Otsu

Original languageEnglish
Article number41
JournalScientific Reports
Issue number1
Early online date7 Jan 2022
Accepted/In press8 Dec 2021
E-pub ahead of print7 Jan 2022

Bibliographical note

Funding Information: This study was supported by the British Heart Foundation (CH/11/3/29051 and RG/16/15/32294), European Research Council (692659), and Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 18H02807 granted to K.O., JSPS KAKENHI Grant Numbers 18H06227, 19K21327 and Takeda Science Foundation granted to M.T., JSPS KAKENHI Grant Number 19K23968 granted to R. K-T, JSPS KAKENHI Grant Number 21K08104 granted to H.N. and JSPS KAKENHI Grant Numbers 20K08448 and a grant from the Setsuro Fujii Memorial, the Osaka Foundation for the Promotion of Fundamental Medical Research granted to O.Y. The funding sources had no involvement in the conduct of the research or preparation of the article. Publisher Copyright: © 2022, The Author(s).

King's Authors


Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.

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