Abstract
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 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 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.
Highlights
Autophagy is an evolutionarily conserved pathway that targets cytoplasmic contents to the lysosome for degradation (Wang and Hill, 2015; Wang and Cui, 2017; Sciarretta et al, 2018)
To determine a causative role of autophagy in the regulation of cardiomyopathy and nuclear factor erythroid 2-related factor (Nrf2)-mediated dichotomy in pressure overload (PO) hearts, we determined the impact of cardiac specific autophagy inhibition via CR-Atg5KO on Transverse Aortic Arch Constriction (TAC)-induced cardiac remodeling and dysfunction as well as Nrf2-mediated dichotomy (Qin et al, 2016) in adult mice
Transverse aortic arch constriction caused around 20% mortality in Control MerCreMer+ (Ctl) mice as described elsewhere (Qin et al, 2016) and it was slightly increased by additional Nrf2 knockout (Nrf2KO) (25%) (Figure 1A), suggesting Nrf2-mediated protection
Summary
Autophagy is an evolutionarily conserved pathway that targets cytoplasmic contents to the lysosome for degradation (Wang and Hill, 2015; Wang and Cui, 2017; Sciarretta et al, 2018). Depending on the nature of stress and timing of assessment, activation of cardiac autophagy has been proposed to be either adaptive or maladaptive (Wang and Hill, 2015; Wang and Cui, 2017; Sciarretta et al, 2018). Most of the recent studies have shown that autophagy activation is likely an adaptive response in the hearts after pressure overload (PO hearts) (Wang and Cui, 2017; Sciarretta et al, 2018). The precise role of autophagy in stressed hearts remains to be investigated and it may not be fully understood until the signaling network of cardiac autophagy is completely mapped
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