Abstract 130: ATP Release Drives the Immune Responses Associated With Hypertension

Abstract

Inflammation is critical in progression of hypertension. However, how an elevated blood pressure (BP) initiates inflammation is unknown, as are the precise effects of high BP on the immune responses. To study this, we first challenged mice with antigen ovalbumin (OVA). Two-fold more OVA-specific CD8 + T cells were present in the blood (2.7 ± 0.23% vs. 1.2 ± 0.47%) and spleen (2.62 ± 0.31% vs. 1.31 ± 0.17%) of angiotensin (Ang) II induced hypertensive mice as compared to those of normotensive controls. To address whether the over-activation of T cell-mediated immune responses is pathogenic, two models of autoimmune disease were studied. RIP-mOVA is a transgenic mouse line that expresses OVA in pancreatic islet β cells. When OVA-specific OT-I T cells were infused into Rip-mOVA mice, the animals with hypertension induced by either Ang II or L-NAME developed more severe diabetes (blood glucose (mg/dl): Ang II 331, L-NAME 315 vs. Control 168). Concanavalin A-induced hepatitis was also significantly worsened by hypertension as compared to the pathology observed in normotensive mice. After examining the characteristics of T cells and antigen presenting cells (APCs), we found that the most distinguishable difference in hypertensive mice was the upregulation of CD86 on APCs. Blocking CD86 by antibody completely abrogated the elevated immune responses in hypertensive mice. To understand what causes CD86 upregulation in APCs of hypertensive mice, we studied damage-associated molecular patterns and found that plasma ATP levels rose as early as 3 days after the induction of hypertension and reached from about 1μM of baseline to a peak level of 3 μM after 2 weeks of hypertension, which exactly parallels the kinetics of CD86 elevation on APCs. Hydrolyzing ATP or blocking its P2X 7 receptor normalized APC CD86 expression and eliminated hypertension-induced T cell over-activation. Further, untreated human hypertensive patients have substantially elevated plasma ATP levels (2.21 ± 0.99 μM, n = 27) compared to treated hypertensive patients (0.94 ± 0.34 μM, n = 17) or normotensive controls (0.63 ± 0.38 μM, n =30). A linear trend was observed between ATP levels and BP among all subjects. These studies indicate ATP is critical in initiating hypertension-associated inflammation.