Role of Redox-Mediated Activation of NFkappaB and AP-1 in Neurogenic Hypertension

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DESCRIPTION (provided by applicant): Human essential hypertension is characterized by sustained increases in sympathetic nerve activity. Exacerbation of angiotensin II (Ang-ll) signaling in the CNS has emerged as a primary culprit driving this chronic neuro-cardiovascular dysfunction, although the underlying molecular substrates are poorly understood. Recently we discovered that redox signaling in the CNS plays a primary role in the long-term effects of Ang-ll on blood pressure and sympathetic outflow. Furthermore, our studies demonstrate that chronic oxidative stress in central cardiovascular pathways is involved in the pathogenesis of hypertension and heart failure. The molecular mechanisms by which excessive oxidant production translates into long-lasting effects on central neural pathways controlling blood pressure are unknown. One way that transient ligand/receptor signals such as Ang-ll are transformed into long-term genetic changes is through activation of specific inducible transcription factors. Nuclear factor kappaB (NFkappaB) and activator protein 1 (AP-1) are important redox-sensitive transcription factors that mediate lasting changes in CNS function. Our preliminary in vivo bioluminescence imaging studies reveal a dramatic bi-phasic activation profile of NFkappaB and AP-1 in the brain of mice during the evolution of systemic Ang-ll "slow-pressor" hypertension. Building on this and also extending our studies to other models of brain Ang-ll-dependent hypertension, we will address the overall hypothesis that redox-mediated activation of NFkappaB and AP-1 in key CNS nuclei is causative molecular events in the pathogenesis of neurogenic hypertension and related autonomic dysfunction. Using a combination of live animal molecular imaging for serial tracking of NF?B and AP-1 activation, brain site-specific viral delivery of oxidant scavenging and dominant-suppressor genes, and integrative cardiovascular physiology in mice, we will perform the following studies: Aim 1) Spatiotemporally map and quantify NFkappaB and AP-1 activation in CNS cardiovascular nuclei of mice with Ang-ll slow-pressor, renovascular (2K1C) and life-long (human renin/human angiotensinogen) hypertension; Aim 2) Dissect the role of superoxide and H2O2 in Ang-ll-stimulated induction of NFkappaB and AP-1 activity in central cardiovascular circuits; Aim 3) Determine the functional role of central NFkappaB and AP-1 activation in the pathogenesis of neurogenic hypertension and related neuro-cardiovascular sequelae. This research has the potential to fundamentally advance our understanding of mechanisms linking the nervous system with cardiovascular disease, and could have important implications for developing novel therapeutic strategies for neurogenic hypertension and related disorders. A further strength of this project is the combination of live animal molecular imaging and sophisticated physiological genomic strategies.