A3590 Plasma ATP level mediates the immune response to hypertension

Abstract

Objectives: This study elucidates the mechanism by which an increase in blood pressure induces and increased inflammatory response. Methods: The detailed T cell response to ovalbumin (OVA) immunization, and to two models of autoimmune disease, were studied in normotensive and AngII or L-NAME induced hypertensive mice. The interaction of T cells and APCs was characterized to determine the cells and precise signals responsible for the heightened immune reactivity in hypertension. Newly presenting and treated hypertensive patients were also studied. Results: Elevated CD8+ and CD4+T cell responses specific to OVA were observed in hypertensive mice. RIP-mOVA transgenic mice express membrane-bound OVA in pancreatic islet β cells. When OVA-specific OT-I T cells were infused into RIP-mOVA mice, the hypertensive mice had significantly more OT-I T cell infiltration into the islets and developed diabetes more rapidly than normotensive RIP-mOVA mice. Concanavalin A induced hepatitis was significantly worsened by hypertension as compared to disease in normotensive mice. More effective APC presentation of antigen, but not differences in intrinsic T cell signaling, is a major instigator of the increased T cell response in hypertension. The key difference in the immune system of hypertensive mice is blood pressure mediated up-regulation of CD86 on APCs, which is triggered by increased plasma ATP levels. Hypertensive humans have high plasma ATP but blood pressure lowering reduces plasma ATP levels to control levels. Conclusion: Hypertension induces biochemical and immune changes that intensify inflammation. Our data indicate ATP and APC CD86 as causative and as potential loci to control hypertension induced tissue inflammation.