Ps-bpb04-2: p2rx7 deficiency or p2rx7 antagonism blunts angiotensin ii-induced hypertension, vascular injury and cd8+ t cell activation

Objectives: Innate and adaptive immune cells contribute to hypertension and end-organ damage. High blood pressure (BP) causes cardiovascular injury and the release of damage-associated molecule patterns such as adenosine triphosphate (ATP). ATP can bind to the purinergic receptor P2X7 (P2RX7) on innate immune cells triggering interleukin-1β; release, which drives further immune activation. Elevated plasma ATP levels was observed in hypertensive patients. We hypothesized that P2rx7 knockout or P2RX7 antagonism would blunt angiotensin II (AngII)-induced BP elevation and cardiovascular injury through decreased immune activation. Design and method: Ten-to-12-week-old male C57BL/6J wild-type (WT) and P2rx7-/- mice were infused or not with AngII (1000 ng/kg/min) for 14 days. A second group of AngII-infused WT mice was also infused with the P2RX7 antagonist AZ10606120 (694 ng/kg/min) or vehicle. BP was determined by telemetry, plasma ATP using a bioluminescence assay, mesenteric artery function using pressurized myography, cardiac left ventricle (LV) function and mass by ultrasound and activated immune T cell infiltration in aortic perivascular adipose tissue (PVAT) by flow cytometry. Results: Plasma ATP was 2.2 fold higher in AngII-infused compared to sham-treated mice ( P < 0.05). AngII-induced systolic BP elevation was reduced by P2rx7 deficiency (12 mm Hg, P < 0.05) or P2RX7 antagonism (27 mm Hg, P < 0.01). AngII induced a 26% decrease in LV fractional shortening (FS, P < 0.05) and a 1.5 fold increase in LV mass/body weight (BW) in WT mice ( P < 0.001), which were exaggerated in P2rx7-/- mice (FS: 38% lower and LVmass/BW: 1.14 fold higher, P < 0.05), but not in mice receiving AZ10606120. AngII treatment caused a 26% reduction in the dilatation response of mesenteric arteries to acetylcholine in WT mice ( P < 0.05), but not in P2rx7-/- or AZ10606120-treated mice. AngII promoted a 3.8 fold increase in CD69 + CD8 + T cell infiltration in aortic PVAT of WT mice ( P < 0.001), but not in P2rx7-/- or AZ10606120-treated mice. Conclusion: P2rx7 knockout or antagonism attenuates AngII-induced BP elevation, vascular injury, and infiltration of activated CD8 + T cells into aortic PVAT. P2rx7 knockout exacerbated AngII-induced cardiac dysfunction and hypertrophy, whereas P2RX7 antagonism did not.