Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice

• Published in: Scientific reports Vol. 10; no. 1; p. 13926
• Main Authors: Shimoda, Kakeru, Nishimura, Akiyuki, Sunggip, Caroline, Ito, Tomoya, Nishiyama, Kazuhiro, Kato, Yuri, Tanaka, Tomohiro, Tozaki-Saitoh, Hidetoshi, Tsuda, Makoto, Nishida, Motohiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.08.2020; Nature Publishing Group
• Subjects: 692/4019/592/1540; 692/699/75/230; Cardiomyocytes; Cell death; Congestive heart failure; Doxorubicin; Fibrosis; Heart failure; Humanities and Social Sciences; Mortality; multidisciplinary; Neonates; Oxidative stress; Pressure; Science; Science (multidisciplinary); Uridine
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70956-5

Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y 6 receptor (P2Y 6 R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y 6 R prevents or promotes heart failure. We demonstrate that inhibition of P2Y 6 R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y 6 R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y 6 R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y 6 R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y 6 R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y 6 R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y 6 R exacerbates pressure overload-induced heart failure in mice, although P2Y 6 R in cardiomyocytes contributes to the progression of cardiac fibrosis.