Regulation of Mitochondrial Redox Systems in T-lymphocytes During Hypertension

University Of Nebraska Medical Center, Omaha NE

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Abstract

DESCRIPTION (provided by applicant): This project will investigate the influence of mitochondrial superoxide (O 2?-) in T-lymphocytes on their activation in the pathogenesis of hypertension. Reactive oxygen species, mainly O 2 ?-, have been elucidated as key molecular intermediates in angiotensin II (AngII)-dependent hypertension. Recently, the immune system, particularly T-lymphocyte activation, has proven causal in AngII-mediated hypertension by exacerbating a pro- inflammatory environment; however, the role of O 2 ?- in mediating intracellular signaling pathways in AngII-stimulated T-lymphocytes remains unclear. In other cell types, mitochondria have been identified as a key source of AngII-induced O2 ?- production, as over-expression of the mitochondrially-localized O2 ?- scavenging enzyme manganese superoxide dismutase (MnSOD) attenuates AngII-mediated O2?- flux. Our preliminary data suggest mitochondria are also a source of O2 ?- in AngII-stimulated T-lymphocytes. Herein, we hypothesize that mitochondrially-produced O2 ?- mediates intracellular T-lymphocyte signaling leading to their activation and enhanced production of cytokines during AngII-mediated hypertension. In Specific Aim 1, we will investigate a causal source of mitochondrial O2?- in mouse primary T-lymphocytes stimulated with AngII. Promising candidate sources include the NADPH oxidase (NOX) enzymes, MnSOD, and the electron transport chain. Specific Aim 2 will examine how AngII carries out signal transduction in T-lymphocytes. Using microarray and cytokine array technology, we will perform a comprehensive analysis of signal transduction pathways, which we will garner specific second messengers and transcription factors to further validate. We will employ the use of MnSOD-deficient and MnSOD-overexpressing mouse models to understand the contribution of mitochondrial O2 ?- to AngII-mediated T-lymphocyte intracellular signaling. Finally, Specific Aim 3 will examine physiological parameters of altered mitochondrial O2 ?- in T-lymphocytes in vivo. By examining mean arterial pressure (MAP) and heart rate (HR) in mice with perturbed mitochondrial O2 ?- specifically in T-lymphocytes, we will obtain in vivo endpoints that will provide a direct connection to hypertension. Overall, this project will further the understanding of the immune system contribution to hypertension, the redox based mechanisms underlying this contribution, and provide potential new targets for pharmaceutical therapy that are currently unacknowledged in hypertension.