Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency

Abstract

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 while switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction (TAC), 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. TAC-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 upregulation of angiotensinogen (Agt) only in the autophagy impaired heart after TAC. 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 as well as 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.

TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux

“…Therefore, the conclusions drawn from the present study have implication in a much broader spectrum of cardiac disorders than cardiac proteinopathy. To this end, experimental evidence is rapidly emerging that inadequate lysosomal removal of autophagosomes as reflected by the co-existence of elevated LC3-II with decreased LC3-II flux, is a shared phenomenon during the progression to heart failure from common forms of etiology such as ischemic heart disease [44], pressure overloaded cardiac hypertrophy [45], and diabetic cardiomyopathies [46]; hence, optimizing the ALP or the coordinate activation of both the formation and the removal of autophagosomes in the heart has been suggested as potential therapeutic strategy to treat these life-threatening conditions. With the exception of ATG7 overexpression and, to some extent, of Beclin1 overexpression [6, 47], means used to increase or optimize ALP flux, such as mTORC1 inhibitors (rapamycin or its homologs), AMPK activators (e.g., metformin), and even starvation and exercise, can hardly be ALP-specific because they all can elicit many other actions favorable or unfavorable to cardiomyocytes [4].…”

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

“…2, 3 However, it is worthy note that among the many reports on alterations of cardiac autophagy, only a few have emphasized that inadequate lysosomal degradation could be a potential underlying cause for the observed increases in autophagosomes. 4–9 This is because the concept “autophagic flux” was not widely recognized then and, as a result, it often was not vigorously assessed. 10 …”

Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress

“…The non-receptor protein tyrosine kinase Fyn phosphorylates Nrf2 inducing its export from the nucleus and proteasomal degradation [ 36 ]. Systemic RKIP -deficiency significantly reduced the nuclear accumulation of the active phosphorylated form Thr12 phospho-Fyn in both groups 5 weeks after surgery and in cultured adult cardiac fibroblasts treated with Ang II (Fig.…”

“…a In pressure-overloaded left-ventricular myocardium of WT N TAC mice Nnt is the dominant source of ROS and phospho-RKIP inhibits GRK2, preventing the down-regulation of AT1-receptor. TAC-induced production of AngII activates the AT1-Jak2-Fyn signaling cascade, leading to phosphorylation of Nrf2, its rapid translocation from the nucleus and degradation by proteasomes [ 36 , 37 ]. The decreased nuclear content of Nrf2 diminishes the expression of antioxidant, cytoprotective ARE-genes.…”

“…b Systemic RKIP -knockout in RKIP − / − N TAC leads to the activation of GRK2, which phosphorylates AT1-receptor, eliciting its internalization and degradation [ 34 ]. The downregulation of AT1-Jak2-Fyn signaling cascade inhibits nuclear export of Nrf2 [ 36 ]. The nuclear accumulation of Nrf2 enhances the expression of ARE-genes reducing myocardial ROS production, cardiac apoptosis, and fibrosis.…”