Hypertension affects 30% of western populations and is a major risk factor for stroke, heart failure and myocardial infarction. Despite this, the etiolgy of most cases of adult hypertension remains undefined. In the past several years, research from several laboratories has shown that inflammation and immunity play an important role in this disease. Mice lacking lymphocytes (RAG1-/- mice) develop blunted hypertension, and are protected from vascular dysfunction and vascular oxidative stress in response to various stimuli, including angiotensin II (ang II), norepinephrine and DOCA-salt. Adoptive transfer of T cells restores hypertension in these animals. I propose that hypertensive stimuli leads to activation of effector CD8+ T cells that mediate cytotoxicity by producing granzyme B. I propose that granzyme B enhances vascular inflammation leading to vascular dysfunction and ultimately hypertension. I also propose that repeated or sustained hypertensive stimuli prime a memory response mediated by CD8+ memory T cells.
In Aim 1, I will test the hypothesis that granzyme B produced by CD8+ T cells augments inflammation leading to vascular oxidative, endothelial dysfunction, and hypertension. To determine the role of granzyme B, I will measure blood pressure and assess vascular function, superoxide (O2*-), and nitric oxide (NO) production in C57Bl/6 and GZMB-/- mice infused with vehicle or ang II (490ng/kg/min). I will also use flow cytometry to examine infiltration of other inflammatory cells into the vasculature. I predict that deletion of granzyme B will protect against hypertension, endothelial dysfunction, and infiltration of inflammatory cells.
In Aim 2, I will test the hypothesis that the interaction between CD27 and CD70 is responsible for the augmented hypertension caused by a second or prolonged exposure to Ang II and that CD4+ cells likely have a role in this memory response. This interaction is known to mediate CD8+ T cell memory. I will infuse C57Bl/6 mice with vehicle or ang II (490ng/kg/min) for two weeks. Three week later, I will treat mice with a low dose of ang II (200 ng/kg/min) and blood pressure will be monitored by telemetry. I will employ an anti-CD70 Ab, CD70-/- mice, and CD4-/- mice that help CD8+ T cells to form a memory response. I predict that repeated or sustained hypertensive stimuli prime a memory response mediated by CD8+ memory T cells and blocking the interaction between CD70 and CD27 will abrogate augmented hypertensive response I observe upon the second exposure to angiotensin II. This work will advance our understanding of hypertension and will provide new therapeutic directions for this disease.
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