scholarly journals Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Huimei Zang ◽  
Weiwei Wu ◽  
Lei Qi ◽  
Wenbin Tan ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Antioxidant Defense ◽  
Myocardial Damage ◽  
Related Factor ◽  
Nrf2 Knockout ◽  
Underlying Mechanisms ◽  
Autophagy Inhibition ◽  
And Oxidative Stress

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 cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO 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 Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

scholarly journals Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Huimei Zang ◽  
Weiwei Wu ◽  
Lei Qi ◽  
Wenbin Tan ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Antioxidant Defense ◽  
Myocardial Damage ◽  
Related Factor ◽  
Nrf2 Knockout ◽  
Underlying Mechanisms ◽  
Autophagy Inhibition ◽  
And Oxidative Stress

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 cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO 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 Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

scholarly journals Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition

2020 ◽  
Vol 21 (21) ◽  
pp. 8105
Author(s):  
Ryan N. Montalvo ◽  
Vivian Doerr ◽  
Oh Sung Kwon ◽  
Erin E. Talbert ◽  
Jeung-Ki Yoo ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Redox Balance ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Sprague Dawley ◽  
Autophagosome Formation ◽  
Underlying Mechanisms ◽  
Autophagy Inhibition

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.

Seabuckthorn Attenuates Cardiac Dysfunction and Oxidative Stress in Isoproterenol-Induced Cardiotoxicity in Rats

2011 ◽  
Vol 30 (6) ◽  
pp. 671-680 ◽  
Author(s):  
Salma Malik ◽  
Sameer Goyal ◽  
Shreesh Kumar Ojha ◽  
Saurabh Bharti ◽  
Saroj Nepali ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Antioxidant Activities ◽  
Cardiac Injury ◽  
Radical Scavenging ◽  
Myocardial Necrosis ◽  
Myocardial Damage ◽  
Ultrastructural Changes ◽  
And Oxidative Stress ◽  
Preventive Role

We investigated the effects of seabuckthorn (SBT) oil in isoproterenol (ISO)-induced cardiotoxicity with reference to hemodynamic, antioxidant, histopathological, and ultrastructural parameters. Rats were administered SBT oil (5, 10, and 20 mL/kg per d) or vehicle orally for 30 days along with ISO (85 mg/kg, subcutaneously, at 24-hour interval) on 29th and 30th day. On 31st day, ISO control rats showed cardiac dysfunction, increased lipid peroxidation, depletion of cardiac injury marker enzymes, and antioxidant activities. Myocardial necrosis, edema, and inflammation were evident from the light microscopic and ultrastructural changes. Seabuckthorn oil at the dose of 20 mL/kg per d significantly modulates hemodynamic and antioxidant derangements. The preventive role of SBT oil on ISO-induced cardiotoxicity was reconfirmed by histopathological and ultrastructural examinations. Thus, the present study reveals that SBT oil mitigates myocardial damage in ISO-induced cardiac injury in rats by maintaining hemodynamic, biochemical, histopathological, and ultrastructural perturbations owing to its free radical scavenging and antioxidant activities.

scholarly journals Tanshinone I Inhibits Oxidative Stress–Induced Cardiomyocyte Injury by Modulating Nrf2 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-Ting Wu ◽  
Ling-Peng Xie ◽  
Yue Hua ◽  
Hong-Lin Xu ◽  
Guang-Hong Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Knockout Mice ◽  
Salvia Miltiorrhiza ◽  
Mapk Signaling ◽  
Related Factor ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Tanshinone I ◽  
Nrf2 Knockout ◽  
And Oxidative Stress

Cardiovascular disease, a disease caused by many pathogenic factors, is one of the most common causes of death worldwide, and oxidative stress plays a major role in its pathophysiology. Tanshinone I (Tan I), a natural compound with cardiovascular protective effects, is one of the main active compounds extracted from Salvia miltiorrhiza. Here, we investigated whether Tan I could attenuate oxidative stress and oxidative stress–induced cardiomyocyte apoptosis through Nrf2/MAPK signaling in vivo and in vitro. We found that Tan I treatment protected cardiomyocytes against oxidative stress and oxidative stress–induced apoptosis, based on the detection of relevant oxidation indexes such as reactive oxygen species, superoxide dismutase, malondialdehyde, and apoptosis, including cell viability and apoptosis-related protein expression. We further examined the mechanisms underlying these effects, determining that Tan I activated nuclear factor erythroid 2 (NFE2)–related factor 2 (Nrf2) transcription into the nucleus and dose-dependently promoted the expression of Nrf2, while inhibiting MAPK signaling activation, including P38 MAPK, SAPK/JNK, and ERK1/2. Nrf2 inhibitors in H9C2 cells and Nrf2 knockout mice demonstrated aggravated oxidative stress and oxidative stress–induced cardiomyocyte injury; Tan I treatment suppressed these effects in H9C2 cells; however, its protective effect was inhibited in Nrf2 knockout mice. Additionally, the analysis of surface plasmon resonance demonstrated that Tan I could directly target Nrf2 and act as a potential Nrf2 agonist. Collectively, these data strongly indicated that Tan I might inhibit oxidative stress and oxidative stress–induced cardiomyocyte injury through modulation of Nrf2 signaling, thus supporting the potential therapeutic application of Tan I for oxidative stress–induced CVDs.

scholarly journals Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts

2021 ◽  
Vol 12 ◽  
Author(s):  
Weiwei Wu ◽  
Qingyun Qin ◽  
Yan Ding ◽  
Huimei Zang ◽  
Dong-Sheng Li ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Pressure Overload ◽  
Myocardial Damage ◽  
Nuclear Accumulation ◽  
Related Factor ◽  
Adult Mice ◽  
Extracellular Signal ◽  
Mechanistic Investigation ◽  
Autophagy Inhibition

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.

scholarly journals Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Siying Li ◽  
Wenjuan Wang ◽  
Ting Niu ◽  
Hui Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adverse Effects ◽  
Cardiac Dysfunction ◽  
Protein Aggregates ◽  
Autophagic Flux ◽  
Related Factor ◽  
Causative Role ◽  
Myocardial Oxidative Stress ◽  
Underlying Mechanisms

The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.

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