Graduation Date

Spring 5-9-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Irving Zucker

Abstract

Sympatho-excitation is a key characteristic in cardiovascular diseases such as chronic heart failure (CHF) and primary Hypertension (HTN). Evidence suggests that increased sympathetic tone is closely related to activation of the Renin-Angiotensin-Aldosterone system (RAAS) in the central nervous system. An underlying mechanism for sympatho-excitation is thought to be oxidative stress resulting from Angiotensin II (AngII) type 1 receptor (AT1R) activation. Over the past several decades, pharmacological targeting of components of the RAAS have been used as standard therapy in CHF and HTN. However, additional therapeutic strategies are necessary to control these diseases. Oxidative stress is regulated, in part, by the balance between components of the RAAS and the ability of the system to scavenge oxygen radicals. Over the past decade, Nuclear factor E2-related factor 2 (Nrf2) has emerged as an important transcriptional regulator that maintains redox homeostasis by governing a broad array of antioxidant genes in response to oxidant stress. Central Nrf2 dysregulation has been found in animals with CHF and HTN. To determine if Nrf2 contributes to decreased antioxidant defense and increased sympathetic nerve activity (SNA) in CHF, we upregulated Nrf2 in the rostral ventrolateral medulla (RVLM) in C57BL/6 mice and evaluated their hemodynamic and sympathetic function in the CHF state. We found that (1) Nrf2 and two target proteins, NAD(P)H dehydrogenase [quinone] 1 (NQO1) and Heme oxygenase (HO-1) in the RVLM were significantly lower in CHF compared to Sham mice; (2) Urinary norepinephrine (NE) excretion in CHF mice was markedly reduced following Nrf2 upregulation; (3) CHF mice overexpressing Nrf2 exhibited an enhancement in spontaneous baroreflex gain and a decrease in basal renal SNA. In an attempt to understand the antioxidant function of the RAAS we examined the role of Angiotensin converting enzyme 2 (ACE2) in a model of central AngII-induced HTN. Despite its direct enzymatic effect on AngII, ACE2 has been shown to reduce oxidative stress and to be sympatho-inhibitory. It has been demonstrated that animals with CHF exhibit increased Angiotensin converting enzyme (ACE) and decreased ACE2 in the RVLM. We hypothesized that overexpression of ACE2 in the brain reduces the sympathetic and blood pressure (BP) responses to central AngII by activation of Nrf2 and enhancing antioxidant enzyme expression. To illuminate the role of Nrf2 in the central regulation of SNA in response to central AngII, we assessed Nrf2 changes in the RVLM in SynhACE2 mice treated with ICV AngII infusion. Mice with central overexpression of ACE2 inhibited the pressor and sympathetic responses to central AngII. We found that Nrf2 was upregulated in the RVLM in SynhACE2 mice, and that pharmacological upregulation of central Nrf2 had a significant impact on BP in response to central AngII. Overall, the experiments described in this dissertation showed that selectively upregulating Nrf2 in the RVLM attenuates sympatho-excitation in CHF mice. We also describe a novel role of interplay between central AngII, ACE2 and Nrf2 in the regulation of sympatho-excitation in central HTN. While not definitive, these studies suggest a role for ACE2 and Nrf2 as targets for therapy in CHF and HTN.

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