PMID- 32948607
OWN - NLM
STAT- MEDLINE
DCOM- 20210126
LR  - 20211203
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 69
IP  - 12
DP  - 2020 Dec
TI  - Autophagy Inhibition Enables Nrf2 to Exaggerate the Progression of Diabetic 
      Cardiomyopathy in Mice.
PG  - 2720-2734
LID - 10.2337/db19-1176 [doi]
AB  - 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.
CI  - (c) 2020 by the American Diabetes Association.
FAU - Zang, Huimei
AU  - Zang H
AD  - Department of Cell Biology and Anatomy, School of Medicine, University of South 
      Carolina, Columbia, SC.
FAU - Wu, Weiwei
AU  - Wu W
AD  - Department of Cell Biology and Anatomy, School of Medicine, University of South 
      Carolina, Columbia, SC.
FAU - Qi, Lei
AU  - Qi L
AD  - Department of Cell Biology and Anatomy, School of Medicine, University of South 
      Carolina, Columbia, SC.
FAU - Tan, Wenbin
AU  - Tan W
AD  - Department of Cell Biology and Anatomy, School of Medicine, University of South 
      Carolina, Columbia, SC.
FAU - Nagarkatti, Prakash
AU  - Nagarkatti P
AD  - Department of Pathology, Microbiology and Immunology, School of Medicine, 
      University of South Carolina, Columbia, SC.
FAU - Nagarkatti, Mitzi
AU  - Nagarkatti M
AD  - Department of Pathology, Microbiology and Immunology, School of Medicine, 
      University of South Carolina, Columbia, SC.
FAU - Wang, Xuejun
AU  - Wang X
AD  - Division of Basic Biomedical Sciences, University of South Dakota Sanford School 
      of Medicine, Vermillion, SD.
FAU - Cui, Taixing
AU  - Cui T
AUID- ORCID: 0000-0002-9528-7299
AD  - Department of Cell Biology and Anatomy, School of Medicine, University of South 
      Carolina, Columbia, SC taixing.cui@uscmed.sc.edu.
LA  - eng
SI  - figshare/10.2337/figshare.12937733
GR  - P01 AT003961/AT/NCCIH NIH HHS/United States
GR  - R01 AR073172/AR/NIAMS NIH HHS/United States
GR  - R01 HL131667/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200918
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Autophagy/*physiology
MH  - Cell Line
MH  - Diabetic Cardiomyopathies/*pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Myoblasts
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Rats
PMC - PMC7679777
EDAT- 2020/09/20 06:00
MHDA- 2021/01/27 06:00
PMCR- 2021/12/01
CRDT- 2020/09/19 05:28
PHST- 2019/11/26 00:00 [received]
PHST- 2020/09/10 00:00 [accepted]
PHST- 2020/09/20 06:00 [pubmed]
PHST- 2021/01/27 06:00 [medline]
PHST- 2020/09/19 05:28 [entrez]
PHST- 2021/12/01 00:00 [pmc-release]
AID - db19-1176 [pii]
AID - 191176 [pii]
AID - 10.2337/db19-1176 [doi]
PST - ppublish
SO  - Diabetes. 2020 Dec;69(12):2720-2734. doi: 10.2337/db19-1176. Epub 2020 Sep 18.