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Purinergic P2Y6 receptors in cardiovascular stress resistance

[Speaker] Caroline Sunggip:1
[Co-author] Motohiro Nishida:2, Akiyuki Nishimura:2, Takuro Numaga Tomita:2, Hitoshi Kurose:3, Bernard Robaye:4
1:Biomedical Sciences and Therapeutics, Faculty of Medicine and Health Sciences, University Malaysia Sabah, Malaysia, 2:Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan, 3:Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan, 4:Institute of Interdisciplinary Research, School of Medicine, Université Libre de Bruxelles, Gosselies 6041, Belgium., Belgium

Background: Arterial remodeling and endothelial dysfuntions are defining features of age-dependent hypertension and the molecular key determinant of this phenomenon involves oxidative stress induced-dysregulation of protective signaling pathways. Purinergic receptors (P2YRs), activated by adenine, uridine nucleotides and nucleotide sugars, play pivotal roles in cardiovascular homeostasis. P2Y6R, an inflammation inducible G protein-coupled receptor is ubiquitously expressed in cardiovascular system and was shown to play significant role in vascular tone regulation. Study in mice shows that P2Y6R-G12/13 signaling activation triggers pressure overload-induced cardiac fibrosis, an event speculated to be the upstream mediator of Ang II Type 1 receptor (AT1R) signaling. Here, we inverstigate the role of P2Y6R in Ang II-induced pathophysiology during aging in mice model.

Methods: P2Y6R knockout mice and littermate control were infused with Ang II for 4 weeks. Blood pressure was monitored weekly. At the end of experimental period, abdominal aorta were isolated and tested for vascular remodeling and endothelial function. in vitro studies on smooth muscle cells were carriend out to investigate the interaction between P2Y6R and AT1R.

Results: We found that deletion of P2Y6R attenuated Ang II-induced increase in blood pressure, vascular remodeling, oxidative stress and endothelial dysfunctions in mice. P2Y6R promoted Ang II-induced hypertension and vascular remodeling in mice ina an age-dependent manner. P2Y6R abundance increased with age in vascular smooth muscle cells. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein-dependent vascular hypertrophy but reduces beta arrestin-dependent AT1R internalization. Moreover, the age-related formation of heterodimer between AT1R and P2Y6R was disrupted by MRS2578, a P2Y6R-selective inhibitor.

Conclusion: These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II. Targeting P2Y6R oligomerization could be a new strategy to reduce the risk of age associated cardiovacular diseases.


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