PMID- 37961034
OWN - NLM
STAT- MEDLINE
DCOM- 20240111
LR  - 20240111
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Linking)
VI  - 26
IP  - 2
DP  - 2024 Feb
TI  - FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control 
      in diabetic cardiomyopathy.
PG  - 732-744
LID - 10.1111/dom.15369 [doi]
AB  - AIMS: To investigate the role of FOXO1 in STAT3 activation and mitochondrial 
      quality control in the diabetic heart. METHODS: Type 1 diabetes mellitus (T1DM) 
      was induced in rats by a single intraperitoneal injection of 60 mg . kg(-1) 
      streptozotocin (STZ), while type 2 diabetes mellitus (T2DM) was induced in rats 
      with a high-fat diet through intraperitoneal injection of 35 mg . kg(-1) STZ. 
      Primary neonatal mouse cardiomyocytes and H9c2 cells were exposed to low glucose 
      (5.5 mM) or high glucose (HG; 30 mM) with or without treatment with the FOXO1 
      inhibitor AS1842856 (1 muM) for 24 hours. In addition, the diabetic db/db mice 
      (aged 8 weeks) and sex- and age-matched non-diabetic db/+ mice were treated with 
      vehicle or AS1842856 by oral gavage for 15 days at a dose of 5 mg . kg(-1) 
       . d(-1) . RESULTS: Rats with T1DM or T2DM had excessive cardiac FOXO1 
      activation, accompanied by decreased STAT3 activation. Immunofluorescence and 
      immunoprecipitation analysis showed colocalization and association of FOXO1 and 
      STAT3 under basal conditions in isolated cardiomyocytes. Selective inhibition of 
      FOXO1 activation by AS1842856 or FOXO1 siRNA transfection improved STAT3 
      activation, mitophagy and mitochondrial fusion, and decreased mitochondrial 
      fission in isolated cardiomyocytes exposed to HG. Transfection with STAT3 siRNA 
      further reduced mitophagy, mitochondrial fusion and increased mitochondrial 
      fission in HG-treated cardiomyocytes. AS1842856 alleviated cardiac dysfunction, 
      pathological damage and improved STAT3 activation, mitophagy and mitochondrial 
      dynamics in diabetic db/db mice. Additionally, AS1842856 improved mitochondrial 
      function indicated by increased mitochondrial membrane potential and adenosine 
      triphosphate production and decreased mitochondrial reactive oxygen species 
      production in isolated cardiomyocytes exposed to HG. CONCLUSIONS: Excessive FOXO1 
      activation during diabetes reduces STAT3 activation, with subsequent impairment 
      of mitochondrial quality, ultimately promoting the development of diabetic 
      cardiomyopathy.
CI  - (c) 2023 John Wiley & Sons Ltd.
FAU - Zhou, Lu
AU  - Zhou L
AUID- ORCID: 0000-0002-7274-8910
AD  - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
FAU - Su, Wating
AU  - Su W
AD  - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
FAU - Wang, Yafeng
AU  - Wang Y
AD  - Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Zhang, Yuefu
AU  - Zhang Y
AD  - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
FAU - Xia, Zhongyuan
AU  - Xia Z
AD  - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
FAU - Lei, Shaoqing
AU  - Lei S
AD  - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
LA  - eng
GR  - NSFC 81700733/National Natural Science Foundation of China/
GR  - NSFC 81772049/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20231114
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - IY9XDZ35W2 (Glucose)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Foxo1 protein, rat)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Stat3 protein, rat)
RN  - 0 (Stat3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Rats
MH  - *Diabetes Mellitus, Type 1/complications/metabolism
MH  - *Diabetes Mellitus, Type 2/complications/metabolism
MH  - *Diabetic Cardiomyopathies
MH  - Glucose/metabolism
MH  - Mitochondria
MH  - Myocytes, Cardiac/metabolism
MH  - RNA, Small Interfering/therapeutic use
OTO - NOTNLM
OT  - FOXO1
OT  - STAT3
OT  - diabetic cardiomyopathy
OT  - mitochondrial fission
OT  - mitochondrial fusion
OT  - mitophagy
EDAT- 2023/11/14 06:42
MHDA- 2024/01/09 06:42
CRDT- 2023/11/14 03:48
PHST- 2023/10/30 00:00 [revised]
PHST- 2023/07/05 00:00 [received]
PHST- 2023/10/30 00:00 [accepted]
PHST- 2024/01/09 06:42 [medline]
PHST- 2023/11/14 06:42 [pubmed]
PHST- 2023/11/14 03:48 [entrez]
AID - 10.1111/dom.15369 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2024 Feb;26(2):732-744. doi: 10.1111/dom.15369. Epub 2023 
      Nov 14.