Graduation Date

Summer 8-14-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Irving H. Zucker

Abstract

Increased activation of the sympathetic nervous system (SNS) plays an essential role in the pathogenesis of cardiovascular diseases such as chronic heart failure (CHF) and hypertension. Oxidative stress in key brain regions that are involved in maintenance and regulation of sympathetic vasomotor tone has been implicated in mediating this sympathoexcitation. One particular mechanism of oxidative stress-mediated increases in SNS is a reduction of antioxidant enzymes in rostral ventrolateral medulla (RVLM) neurons. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a master regulator of cellular redox homeostasis that impacts the expression of antioxidant gene expression. Recent studies have demonstrated that Nrf2 gene deletion in the RVLM reduces antioxidant enzymes and increases sympathetic outflow, whereas the upregulation of Nrf2 selectively in the RVLM attenuates sympathoexcitation in CHF mice.

Despite current CHF therapy that targets the renin-angiotensin and adrenergic systems, the morbidity and mortality of this disease are still extremely high, even with the best medical management. Exercise training (ExT) is now considered as adjunctive therapy for CHF. Growing evidence indicates that the beneficial effects of ExT in CHF are dependent, at least in part, on augmented central antioxidant capacity, which results in a reduction of sympathetic nervous activity. However, the exact mechanism by which ExT enhances antioxidant activity in central neurons remains unexplored. We hypothesized that Nrf2 plays a key role in modulating antioxidant enzymes in the RVLM and sympathoexcitation in the CHF state. Molecular studies revealed that ExT increased Nrf2 and antioxidant enzymes in the RVLM, and reduced sympathoexcitation in mice with CHF.

Although ExT is an effective and inexpensive way to improve the quality of life in CHF syndrome, low exercise capacity (exercise intolerance) is a major clinical symptom of this syndrome that may hinder the beneficial effects of ExT. Previous studies have shown that increased oxidative stress and reduced antioxidant enzymes in skeletal muscle causes, at least in part, skeletal myopathy, which contributes substantially to exercise intolerance in CHF. However, the mechanism by which antioxidant enzymes are declined in skeletal muscle during CHF is not known. Therefore, we hypothesized that Nrf2 downregulation contributes to the impaired antioxidant defense in skeletal muscle during CHF. We further hypothesized that activation of Nrf2, by curcumin, improves exercise performance in CHF. Indeed, in the CHF mouse model, Nrf2 was downregulated in skeletal muscle, and curcumin treatment was associated with improved exercise capacity and upregulated Nrf2 and antioxidant enzymes in skeletal muscle. Collectively, these data implicate Nrf2 as a key factor in the reduction of sympathoexcitation and improved exercise capacity in the setting of CHF.

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