Induction of Cardiac Pathology: Endogenous versus Exogenous Nrf2 Upregulation

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the endogenous antioxidant response to reactive oxygen species as well as a controller of Phase II detoxification in response to xenobiotics. This amenity to specific external manipulation exploits the binding affinity of Nrf2 for its constitutive repressor and degradation facilitator Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1). Derived from both natural and synthesized origins, these compounds have been extensively tested without definitive beneficial results. Unfortunately, multiple terminated trials have shown a negative side to Nrf2 with regard to cardiac pathologies while animal-based studies have demonstrated cardiomyocyte hypertrophy and heart failure after chronic Nrf2 upregulation. Putatively based on autophagic control of Nrf2 activity-modulating upstream factors, new evidence of miRNA involvement has added complexity to this mechanism. What follows is an extensive survey of Nrf2-regulating exogenous compounds that may promote cardiomyopathy, clinical trial evidence, and a comparison to exercise-induced factors that also upregulate Nrf2 while preventing cardiac pathologies.

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“…Epigenetic factors and interaction with several signaling pathways work in the maintenance of Nrf2 levels. In addition to Keap1, the regulation also happens by three other ubiquitin ligase E3 complexes responsible for the ubiquitylation and degradation of Nrf2 including the Cullin 3 (CUL3)-RING-box protein 1 (RBX1)-KEAP1 complex, which is responsible for the response to electrophilic/OS in the cytosol; the Skp, Cullin, F-box containing complex (SCF /β-TrCP complex), which acts both in the nucleus and in the cytosol through metabolic changes; and, finally, the endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase (HRD1), which is located in the endoplasmic reticulum and ubiquitylates Nrf2 during stress in this cellular compartment [ 110 , 118 , 119 , 120 , 121 ].…”

“…The primary function of Keap1 is to facilitate the degradation of Nrf2 when it is not necessary. However, when OS achieves normal cells, these events trigger the dissociation between Keap1 and Nrf2, dissolving the Nrf2/Keap1 complex and promoting the translocation of Nrf2 to the cells’ nucleus where Nrf2 induces the activation and transcription of a variety of anti-oxidative and anti-inflammatory genes [ 10 , 119 , 120 , 121 , 141 ].…”