| Title: | P2RX7 gene knockout or antagonism reduces angiotensin II-induced hypertension, vascular injury and immune cell activation |
| Journal: | Journal of Hypertension |
| Published: | 27 Jul 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37796207/ |
| DOI: | https://doi.org/10.1097/hjh.0000000000003520 |
Publication 11655
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Abstract
OBJECTIVE: Extracellular ATP is elevated in hypertensive mice and humans and may trigger immune activation through the purinergic receptor P2X7 (P2RX7) causing interleukin-1β production and T-cell activation and memory T-cell development. Furthermore, P2RX7 single nucleotide polymorphisms (SNP) are associated with hypertension. We hypothesized that P2RX7 activation contributes to hypertension and cardiovascular injury by promoting immune activation.</p>
METHODS: Male wild-type and P2rx7-/- mice were infused or not with angiotensin II (AngII) for 14 days. A second group of AngII-infused wild-type mice were co-infused with the P2RX7 antagonist AZ10606120 or vehicle. BP was monitored by telemetry. Cardiac and mesenteric artery function and remodeling were assessed using ultrasound and pressure myography, respectively. T cells were profiled in thoracic aorta/perivascular adipose tissue by flow cytometry. Associations between SNPs within 50 kb of P2RX7 transcription, and BP or hypertension were modeled in 384 653 UK Biobank participants.</p>
RESULTS: P2rx7 inactivation attenuated AngII-induced SBP elevation, and mesenteric artery dysfunction and remodeling. This was associated with decreased perivascular infiltration of activated and effector memory T-cell subsets. Surprisingly, P2rx7 knockout exaggerated AngII-induced cardiac dysfunction and remodeling. Treatment with a P2RX7 antagonist reduced BP elevation, preserved mesenteric artery function and reduced activated and effector memory T cell perivascular infiltration without adversely affecting cardiac function and remodeling in AngII-infused mice. Three P2RX7 SNPs were associated with increased odds of DBP elevation.</p>
CONCLUSION: P2RX7 may represent a target for attenuating BP elevation and associated vascular damage by decreasing immune activation.</p>
11 Authors
- Brandon G. Shokoples
- Olga Berillo
- Kevin Comeau
- Hao Yu Chen
- Akinori Higaki
- Antoine Caillon
- Nathanne S. Ferreira
- James C. Engert
- George Thanassoulis
- Pierre Paradis
- Ernesto L. Schiffrin
1 Application
| Application ID | Title |
|---|---|
| 41025 | Pleiotropic effects of cardiometabolic genetic markers and their interaction with diet and fatty acids in cardiovascular diseases. |
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