P2Y6 receptor exacerbates pressure overload-induced heart failure in mice

[Speaker] Kakeru Shimoda:1,2
[Co-author] Caroline Sunggip:1, Akiyuki Nishimura:1,2, Tomohiro Tanaka:1, Takuro Numaga-Tomita:1,2, Kazuhiro Nishiyama:3, Motohiro Nishida:1,2,3
1:Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Japan, 2:Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Japan, 3:Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan

Background- Purinergic P2Y6 receptor (P2Y6R) is a member of purinergic family G protein-coupled receptor (GPCR) activated by extracellular uridine nucleotides. We previously reported that MRS2578, specific inhibitor of P2Y6R, suppresses cardiac remodeling such as fibrosis and hypertrophy induced by pressure overload (EMBO J., 27, 3104-3115, 2008). We thus hypothesize that P2Y6R deficient mice would show same phenotype, and investigate whether pressure overload-induced heart failure is attenuated in P2Y6R deficient mice.

Methods & Results- We performed transverse aortic constriction (TAC) to induce cardiac pressure overload to P2Y6R deficient mice. Contrary to our expectation, P2Y6R deficiency exacerbated cardiac remodeling induced by pressure overload. Therefore, we speculated that MRS2578 activates P2Y6R-dependent signaling pathway that will be independent from canonical purinergic signaling. We found that treatment of neonatal rat cardiomyocytes (NRCMs) with MRS2578 induced upregulation of superoxide dismutase 2 (SOD2). Next, we administrated MRS2578 to WT or P2Y6R deficient mice, and found that MRS2578-induced upregulation of SOD2 in WT was diminished in P2Y6R deficient mice. We further examined localization of P2Y6R during treatment of MRS2578 in FLAG-P2Y6R-transfected HEK 293 cells using confocal microscopy, and revealed that P2Y6R is translocated from plasma membrane to endoplasmic reticulum after MRS2578 treatment. We further found that MRS2578treatment induced multimer formation of P2Y6R proteins.

Summary- Our data suggest that MRS2578, a P2Y6R-selective antagonist, induces SOD2 expression independently of canonical purinergic signaling pathway. MRS2578-induced changes in localization and protein quality of P2Y6R would trigger the activation of cardioprotective signaling pathways.

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