Abstract

Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.

Details

Title
Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice
Author
Shimoda Kakeru 1 ; Nishimura Akiyuki 2 ; Sunggip Caroline 3 ; Ito Tomoya 4 ; Nishiyama Kazuhiro 5 ; Kato, Yuri 5 ; Tanaka, Tomohiro 6 ; Tozaki-Saitoh Hidetoshi 5 ; Tsuda Makoto 5 ; Nishida Motohiro 7 

 National Institutes of Natural Sciences, National Institute for Physiological Sciences (NIPS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems (ExCELLS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); The Graduate University for Advanced Studies), SOKENDAI (School of Life Science, Okazaki, Japan (GRID:grid.275033.0) (ISNI:0000 0004 1763 208X) 
 National Institutes of Natural Sciences, National Institute for Physiological Sciences (NIPS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems (ExCELLS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); The Graduate University for Advanced Studies), SOKENDAI (School of Life Science, Okazaki, Japan (GRID:grid.275033.0) (ISNI:0000 0004 1763 208X); Kyushu University, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan (GRID:grid.177174.3) (ISNI:0000 0001 2242 4849) 
 National Institutes of Natural Sciences, National Institute for Physiological Sciences (NIPS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); Kyushu University, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan (GRID:grid.177174.3) (ISNI:0000 0001 2242 4849); University Malaysia Sabah, Faculty of Medicine and Health Sciences, Kota Kinabalu, Malaysia (GRID:grid.265727.3) (ISNI:0000 0001 0417 0814) 
 National Institutes of Natural Sciences, National Institute for Physiological Sciences (NIPS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems (ExCELLS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732) 
 Kyushu University, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan (GRID:grid.177174.3) (ISNI:0000 0001 2242 4849) 
 National Institutes of Natural Sciences, National Institute for Physiological Sciences (NIPS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems (ExCELLS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); The Graduate University for Advanced Studies), SOKENDAI (School of Life Science, Okazaki, Japan (GRID:grid.275033.0) (ISNI:0000 0004 1763 208X); National Institutes of Natural Sciences, Center for Novel Science Initiatives (CNSI), Tokyo, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732) 
 National Institutes of Natural Sciences, National Institute for Physiological Sciences (NIPS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems (ExCELLS), Okazaki, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732); The Graduate University for Advanced Studies), SOKENDAI (School of Life Science, Okazaki, Japan (GRID:grid.275033.0) (ISNI:0000 0004 1763 208X); Kyushu University, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan (GRID:grid.177174.3) (ISNI:0000 0001 2242 4849); National Institutes of Natural Sciences, Center for Novel Science Initiatives (CNSI), Tokyo, Japan (GRID:grid.250358.9) (ISNI:0000 0000 9137 6732) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2435028531
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.