Induction of Cardiac Pathology: Endogenous versus Exogenous Nrf2 Upregulation

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiology

Background:

• Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates antioxidant and detoxification responses.
• Nrf2 activity is controlled by its repressor, Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1).
• External compounds targeting Nrf2 have shown limited benefits and potential cardiac risks.

Purpose of the Study:

• To survey exogenous compounds that modulate Nrf2 and may induce cardiomyopathy.
• To review clinical trial evidence regarding Nrf2-targeting drugs and cardiac pathologies.
• To compare Nrf2 upregulation by exogenous compounds versus exercise regarding cardiac effects.

Main Methods:

• Literature review of Nrf2-regulating compounds.
• Analysis of clinical trial data on Nrf2 modulators and cardiac outcomes.
• Comparative analysis of Nrf2 activation mechanisms by drugs and exercise.

Main Results:

• Some Nrf2-activating compounds are linked to adverse cardiac events, including hypertrophy and heart failure in animal models.
• Clinical trials of these compounds have yielded inconclusive or negative results concerning cardiac safety.
• Exercise-induced Nrf2 upregulation appears to confer cardioprotection, contrasting with drug-induced effects.

Conclusions:

• Exogenous Nrf2 activators pose a risk for cardiomyopathy, necessitating careful clinical evaluation.
• The mechanism of Nrf2 regulation differs between exogenous compounds and physiological stimuli like exercise.
• Further research into miRNA involvement and upstream factors is needed to understand Nrf2's complex role in cardiac health.