Abstract | AIMS: To investigate the role of FOXO1 in STAT3 activation and mitochondrial quality control in the diabetic heart. METHODS: 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.
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Authors | Lu Zhou, Wating Su, Yafeng Wang, Yuefu Zhang, Zhongyuan Xia, Shaoqing Lei |
Journal | Diabetes, obesity & metabolism
(Diabetes Obes Metab)
(Nov 14 2023)
ISSN: 1463-1326 [Electronic] England |
PMID | 37961034
(Publication Type: Journal Article)
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Copyright | © 2023 John Wiley & Sons Ltd. |