All ETDs from UAB

Advisory Committee Chair

Rajasekaran Namakkal Soorappan

Advisory Committee Members

Steven Austad

Silvio Litovsky

Rakesh Patel

Steven Pogwizd

Document Type

Dissertation

Date of Award

2023

Abstract

The gain of function of nuclear factor erythroid 2 like 2 (Nrf2), in the absence of oxidative stress (or toxic insults), its pathophysiology arising from the endoplasmic reticulum and exercise intervention to mitigate the pathology are the focal point of this dissertation. Nrf2, when constitutively expressed, has been previously associated with cardiomyopathy. Chapter II investigated the hypothesis that cardiac-specific expression of Nrf2 (mNrf2-TG) would establish a pro-reductive state and trigger adaptive cardiac remodeling by enhancing the basal antioxidant defense. Through RNA profiling and imaging techniques, the study underscored that while acute preconditioning might prove advantageous against oxidative stress, prolonged pro-reductive states might shift adaptation towards pathological remodeling.Chapter III investigated the influence of hyper reductive state on endoplasmic reticulum (ER); an essential cellular mechanism influenced by reductive states. Analyzing the ER transcriptome across various ages in mice with cardiac specific Nrf2 overexpression, a unique ER stress response emerged. This response, characterized by the downregulation of vital protein folding genes and an upregulation of ER-associated degradation (ERAD) iv function, indicates that constant Nrf2 activation adversely impacts the protein folding activity over time. Finally, Chapter 4 elucidated the potential benefits of long-term forced treadmill exercise on cardiomyocyte physiology in the context of chronic Nrf2 activation (hyper reductive state). While exercise did mitigate antioxidant-induced cardiac hypertrophy and partially restored cardiac function, ER stress markers remained largely consistent. Interestingly, exercise seemed to alleviate certain adverse effects of chronic Nrf2 activation by restoring protein quality control mechanisms. Collectively, this thesis attempts to illuminate the nuanced roles of Nrf2 in cardiac physiology, revealing its deleterious effects depending on context and duration of expression. Furthermore, the beneficial potential of exercise in countering the consequences of hyper reductive stress was established. This multi-pronged investigation provides invaluable insights into cardiac health, cellular reductive states, and potential therapeutic interventions for related pathologies.

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