Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research.
Preventive and Genomic Cardiology, McGill University Health Centre Research Institute.
J Hypertens. 2023 Nov 1;41(11):1701-1712. doi: 10.1097/HJH.0000000000003520. Epub 2023 Jul 27.
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.
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.
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.
P2RX7 may represent a target for attenuating BP elevation and associated vascular damage by decreasing immune activation.
细胞外 ATP 在高血压小鼠和人类中升高，可能通过嘌呤能受体 P2X7（P2RX7）触发免疫激活，导致白细胞介素-1β产生和 T 细胞激活及记忆 T 细胞发育。此外，P2RX7 单核苷酸多态性（SNP）与高血压相关。我们假设 P2RX7 激活通过促进免疫激活导致高血压和心血管损伤。
雄性野生型和 P2rx7-/- 小鼠接受或不接受血管紧张素 II（AngII）输注 14 天。第二组 AngII 输注野生型小鼠同时输注 P2RX7 拮抗剂 AZ10606120 或载体。通过遥测监测血压。使用超声和压力肌动描记术分别评估心脏和肠系膜动脉功能和重塑。通过流式细胞术分析胸主动脉/血管周围脂肪组织中的 T 细胞。在 384653 名英国生物银行参与者中对 P2RX7 转录体 50kb 内的 SNP 与 BP 或高血压之间的关系进行建模。
P2rx7 失活减弱了 AngII 诱导的 SBP 升高以及肠系膜动脉功能障碍和重塑。这与血管周围活化和效应记忆 T 细胞亚群浸润减少有关。令人惊讶的是，P2rx7 敲除加剧了 AngII 诱导的心脏功能障碍和重塑。用 P2RX7 拮抗剂治疗可降低 BP 升高，维持肠系膜动脉功能，减少活化和效应记忆 T 细胞血管周围浸润，而不影响 AngII 输注小鼠的心脏功能和重塑。三个 P2RX7 SNP 与 DBP 升高的几率增加相关。
P2RX7 可能代表通过减少免疫激活来减轻 BP 升高和相关血管损伤的靶点。
