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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 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. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction. [ABSTRACT FROM AUTHOR]

Aims: Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation; however, the potential roles of DUBs in the heart remain to be determined. This study was aimed to explore the role of a DUB, ubiquitin carboxyl terminal hydrolyase L1 (UCH-L1) in maladaptive cardiac remodeling and dysfunction. Methods and Results: Maladaptive cardiac remodeling and dysfunction were induced in mice by transverse aortic constriction (TAC). UCH-L1 expression was transiently increased and then declined near to the basal level while impairment of cardiac function proceeded. The upregulation of UCH-L1 was observed in cardiac myocytes and fibroblasts. In primary culture of cardiac fibroblasts, UCH-L1 was upregulated by platelet-derived growth factor (PDGF)-BB and PDGF-DD. Adenoviral overexpession of UCH-L1 inhibited the PDGF-induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3). Further signaling dissection revealed that PDGF-BB posttranscriptional upregulated p21WAF1/Cip1 protein expression, which was inhibited by rapamycin, an activator of autophagy via suppressing mammalian target of rapamycin (mTOR), rather than MG132, a proteasome inhibitor. Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21WAF1/Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts. Conclusion: UCH-L1 facilitates PDGF-BB-induced suppression of autophagic degradation of p21WAF1/Cip1 proteins in cardiac fibroblasts, which may serve as a novel negative feedback mechanism in the control of cardiac fibroblast proliferation contributing to cardiac fibrosis and dysfunction. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction., (© 2015 American Heart Association, Inc.)

Aims: Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation; however, the potential roles of DUBs in the heart remain to be determined. This study was aimed to explore the role of a DUB, ubiquitin carboxyl terminal hydrolyase L1 (UCH-L1) in maladaptive cardiac remodeling and dysfunction., Methods and Results: Maladaptive cardiac remodeling and dysfunction were induced in mice by transverse aortic constriction (TAC). UCH-L1 expression was transiently increased and then declined near to the basal level while impairment of cardiac function proceeded. The upregulation of UCH-L1 was observed in cardiac myocytes and fibroblasts. In primary culture of cardiac fibroblasts, UCH-L1 was upregulated by platelet-derived growth factor (PDGF)-BB and PDGF-DD. Adenoviral overexpession of UCH-L1 inhibited the PDGF-induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3). Further signaling dissection revealed that PDGF-BB posttranscriptional upregulated p21WAF1/Cip1 protein expression, which was inhibited by rapamycin, an activator of autophagy via suppressing mammalian target of rapamycin (mTOR), rather than MG132, a proteasome inhibitor. Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21WAF1/Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts., Conclusion: UCH-L1 facilitates PDGF-BB-induced suppression of autophagic degradation of p21WAF1/Cip1 proteins in cardiac fibroblasts, which may serve as a novel negative feedback mechanism in the control of cardiac fibroblast proliferation contributing to cardiac fibrosis and dysfunction.