The Dark Side of Nrf2 in the Heart

Abstract

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) is a critical transcription factor that regulates the expression of over 1000 genes in the cell under normal and stressed conditions. These transcripts can be categorized into different groups with distinct functions, including antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic degradation, and metabolism. Nevertheless, Nrf2 has been historically considered as a crucial regulator of antioxidant defense to protect against various insult-induced organ damage and has evolved as a promising drug target for the treatment of human diseases, such as heart failure. However, burgeoning evidence has revealed a detrimental role of Nrf2 in cardiac pathological remodeling and dysfunction toward heart failure. In this mini-review, we outline recent advances in structural features of Nrf2 and regulation of Nrf2 activity and discuss the emerging dark side of Nrf2 in the heart as well as the potential mechanisms of Nrf2-mediated myocardial damage and dysfunction.

Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts

“…Nrf2 has been considered as a hermetic factor ( Maher and Yamamoto, 2010 ). However, such a theory that either too much or too little of Nrf2 can lead to pathological endpoints cannot explain Nrf2-mediated cardiac phenotypes ( Zang et al, 2020a ). For example, CR-Nrf2 Tg mice is perfectly normal under physiological conditions, and sustained PO does not result in super-activation of Nrf2 in the heart although Nrf2 activation promotes the PO-induced cardiomyopathy ( Zang et al, 2020a ).…”

“…However, such a theory that either too much or too little of Nrf2 can lead to pathological endpoints cannot explain Nrf2-mediated cardiac phenotypes ( Zang et al, 2020a ). For example, CR-Nrf2 Tg mice is perfectly normal under physiological conditions, and sustained PO does not result in super-activation of Nrf2 in the heart although Nrf2 activation promotes the PO-induced cardiomyopathy ( Zang et al, 2020a ). In the present study, we showed that cardiac specific autophagy inhibition via CR-Atg5KO wiped out Nrf2-mediated cardiac protection while turning on Nrf2-mediated pathological cardiac remodeling and dysfunction, providing direct evidence to demonstrate a critical role autophagy in the control of Nrf2-mediated dichotomy in PO hearts.…”

“…Nuclear factor-erythroid factor 2-related factor 2 (Nrf2), a transcription factor, controls the basal and inducible expression of several hundred genes that can be grouped into several categories with different functions including antioxidant defense, detoxification, inflammatory responses, gene transcription, transporters, protein degradation, and metabolism ( Cui et al, 2016 ; Zang et al, 2020a ). Thus, the functions of Nrf2 spread rather broadly from antioxidant defense to protein quality control and metabolism regulation.…”

“…Historically, Nrf2 has been considered as a master regulator of antioxidant defense, thereby providing protection against diverse cardiomyopathies associated with oxidative stress ( Li et al, 2009a ). However, this notion is challenged by the emerging evidence which revealed a mediator role of Nrf2 in the progression of cardiomyopathies associated with various pathological settings including proteotoxicity associated with aging, myocardial ischemia-reperfusion injury, pressure overload, and type 1 diabetes ( Zang et al, 2020a , b ). Although the precise mechanisms underlying Nrf2-mediated dichotomy in the heart are poorly understood, we observed that activation of Nrf2 is protective ( Li et al, 2009a ) when autophagy is intact in PO hearts, whereas it become detrimental to PO hearts when cardiac autophagy is impaired ( Qin et al, 2016 ).…”

Targeting Nrf2 for the treatment of Duchenne Muscular Dystrophy

“…But can hormesis by overdone? There is burgeoning evidence to suggest that persistent unsolicited Nrf2 overactivation, particularly alongside dysregulated autophagy, can progress cardiac disease despite being initially beneficial for resisting myocardial damage [ 57 ]. Thus, a molecular “tipping-point” clearly exists, which is dependent upon the pathological environment and the proper function and/or amenability to modulation of the downstream cytoprotective events that are governed by Nrf2 (i.e.…”