Purinergic P2Y(6) receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension

Caroline Sunggip, and Akiyuki Nishimura, and Hidetoshi Tozaki-Saitoh, and Tsukasa Shimauchi, and Takuro Numaga-Tomita, and Katsuya Hirano, and Tomomi Ide, and Jean-Marie Boeynaems, and Hitoshi Kurose, and Makoto Tsuda, and Bernard Robaye, and Kazuhide Inoue, and Motohiro Nishida, (2016) Purinergic P2Y(6) receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension. Science Signaling, 9 (411). ra7. ISSN 1937-9145

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Official URL: http://dx.doi.org/10.1126/scisignal.aac9187

Abstract

The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR), promoted Ang II–induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II–induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein–dependent vascular hypertrophy but reduced β-arrestin–dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II–induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin–dependent proliferation to G protein–dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II.

Item Type:Article
Uncontrolled Keywords:Ang II, vascular, receptor, hypertension
Subjects:R Medicine > RB Pathology
Divisions:FACULTY > Faculty of Medicine and Health Sciences
ID Code:13759
Deposited By:IR Admin
Deposited On:09 Aug 2016 12:58
Last Modified:09 Aug 2016 12:58

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