High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

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.

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Faculty Opinions recommendation of Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725879184.793521464 ◽

2016 ◽

Author(s):

George Booz ◽

Raffaele Altara

Keyword(s):

Myocardial Ischemia ◽

Angiotensin Converting Enzyme ◽

Cardiac Dysfunction ◽

High Mobility ◽

High Mobility Group ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2

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

10.2337/figshare.12937733.v1 ◽

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.

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Abstract 3659: High-Mobility Group Box 1 Restores Cardiac Dysfunction after Myocardial Infarction in Transgenic Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_460-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Tatsuro Kitahara ◽

Yasuchika Takeishi ◽

Tetsuro Shishido ◽

Satoshi Suzuki ◽

Shigehiko Kato ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Cardiac Dysfunction ◽

Nuclear Dna ◽

Inflammatory Responses ◽

High Mobility ◽

Left Ventricular ◽

High Mobility Group ◽

Coronary Artery Ligation ◽

Artery Ligation

High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac dysfunction after myocardial infarction, we generated transgenic mouse with cardiac specific overexpression of HMGB1 (HMGB1-Tg) using α-myosin heavy chain (MHC) promoter. The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1 overexpressing hearts. The size of myocardial infarction was smaller in HMGB1-Tg than in Wt mice (figure ). Echocardiography and cardiac catheterization demonstrated that cardiac remodeling and dysfunction after myocardial infarction were prevented in HMGB1-Tg mice compared to Wt mice. Furthermore, survival rate after myocardial infarction in HMGB1-Tg mice was higher than that in Wt mice (figure ). Immunohistochemical staining revealed that capillary and arteriole formations after myocardial infarction were enhanced in HMGB1-Tg mice. We demonstrated the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac dysfunction, and improves survival after myocardial infarction. These results may provide a novel therapeutic approach for left ventricular dysfunction after myocardial infarction.

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