Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts

Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts

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Burgeoning evidence has indicated that normal autophagy is required for nuclear factor erythroid 2-related factor (Nrf2)-mediated cardiac protection whereas autophagy inhibition turns on Nrf2-mediated myocardial damage and dysfunction in a setting of pressure overload (PO).However, such a concept remains to be fully established by a careful genetic interrogation in vivo.This study was designed to validate the hypothesis rumchata proof using a mouse model of PO-induced cardiomyopathy and heart failure, in which cardiac autophagy and/or Nrf2 activity are genetically inhibited.Myocardial autophagy inhibition was induced by cardiomyocyte-restricted (CR) knockout (KO) of autophagy related (Atg) 5 (CR-Atg5KO) in adult mice.CR-Atg5KO impaired cardiac adaptations while exacerbating cardiac maladaptive responses in the setting of PO.

Notably, it also turned off Nrf2-mediated defense while switching on Nrf2-operated tissue damage in PO hearts.In addition, cardiac autophagy inhibition selectively inactivated extracellular signal regulated kinase (ERK), which coincided with increased nuclear accumulation of Nrf2 and ah6789-001 decreased nuclear translocation of activated ERK in cardiomyocytes in PO hearts.Mechanistic investigation revealed that autophagy is required for the activation of ERK, which suppresses Nrf2-driven expression of angiotensinogen in cardiomyocytes.Taken together, these results provide direct evidence consolidating the notion that normal autophagy enables Nrf2-operated adaptation while switching off Nrf2-mediated maladaptive responses in PO hearts partly through suppressing Nrf2-driven angiotensinogen expression in cardiomyocytes.