Autophagy Inhibition Enables Nrf2 to Exaggerate the Progression of Diabetic Cardiomyopathy in Mice

Abstract

Nuclear factor-erythroid factor 2–related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis, and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by a cardiomyocyte-restricted (CR) Nrf2 transgenic approach in mice. Moreover, cardiac autophagy inhibition via CR knockout of autophagy-related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO–induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on an Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

“…In the cardiomyocytes, You et al found that KD contributes to the profibrotic actions in fibroblasts possibly via the mTOR signaling pathway in hypertension [6]. Besides, diabetes could modulate a wide range of cellular processes (e.g., autophagy, oxidative stress, and ferroptosis) in cardiomyocytes and endothelial cells, which could be important in the regulations of fibrosis during DCM development [45,46]. A lack of evidence on these aspects has restricted us to provide full information assessing the way that KD regulates DCM in vivo.…”

Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts

“…The critical downstream effectors of Nrf2-mediated myocardial damage and dysfunction in autophagy-impaired PO hearts remain to be determined. Recently, we demonstrated that CR-Atg5KO exacerbates Nrf2-mediated cardiac pathological remodeling and dysfunction and intensifies Nrf2-driven transcription of a subset of genes, such as acyl-CoA synthetase long-chain family 4 (Acsl4), cluster of differentiation 36 (Cd36), angiotensinogen (Agt), and Kruppel-like factor 9 (Klf9), while suppressing Nrf2-operated transcription of cellular defense genes including glutathione peroxidase 4 (Gpx4) and ferroptosis suppressor protein 1 (Fsp1), also known as apoptosis-inducing factor mitochondria 2 (Aifm2), thereby exaggerating the progression of cardiomyopathy associated with type 1 diabetes ( Zang et al, 2020b ). Whether such autophagy-governed coordination of Nrf2 signaling pathways is also disturbed in PO hearts deserves investigations, thus providing mechanistic insights into the molecular network by which autophagy controls Nrf2-mediated dichotomy in the heart.…”

“…Historically, Nrf2 has been considered as a master regulator of antioxidant defense, thereby providing protection against diverse cardiomyopathies associated with oxidative stress ( Li et al, 2009a ). However, this notion is challenged by the emerging evidence which revealed a mediator role of Nrf2 in the progression of cardiomyopathies associated with various pathological settings including proteotoxicity associated with aging, myocardial ischemia-reperfusion injury, pressure overload, and type 1 diabetes ( Zang et al, 2020a , b ). Although the precise mechanisms underlying Nrf2-mediated dichotomy in the heart are poorly understood, we observed that activation of Nrf2 is protective ( Li et al, 2009a ) when autophagy is intact in PO hearts, whereas it become detrimental to PO hearts when cardiac autophagy is impaired ( Qin et al, 2016 ).…”

Ferroptosis Is a Potential Novel Diagnostic and Therapeutic Target for Patients With Cardiomyopathy

“…Considering that ROS formation promotes ferroptosis, it is very likely that ferroptosis is involved in DCM ( Anandhan et al, 2020 ; Chen et al, 2020 ). Zang et al (2020) showed that diabetes was capable of inducing autophagy deficiency with time, resulting in Nuclear factor-erythroid factor 2-related factor 2 (Nrf2)-mediated defense was turned off. Subsequently, Nrf2-operated pathological program was turned on, which made cells prone to ferroptosis, leading to worsening the progression of DCM ( Zang et al, 2020 ).…”

“… Zang et al (2020) showed that diabetes was capable of inducing autophagy deficiency with time, resulting in Nuclear factor-erythroid factor 2-related factor 2 (Nrf2)-mediated defense was turned off. Subsequently, Nrf2-operated pathological program was turned on, which made cells prone to ferroptosis, leading to worsening the progression of DCM ( Zang et al, 2020 ). This indicated that more attention should be given with regard to ferroptosis mediated by the Nrf2 pathway.…”