Journal
ONCOTARGET
Volume 8, Issue 46, Pages 80612-80624Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20811
Keywords
circadian clock; Bmal1 gene; autophagy; diabetic cardiomyopathy; cardiomyocyte injury
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Funding
- National Natural Science Foundation of China [81400217, 81570345]
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High-glucose-induced cardiomyocyte injury is the major cause of diabetic cardiomyopathy, but its regulatory mechanisms are not fully understood. Here, we report that a circadian clock gene, brain and muscle Arnt-like 1 (Bmal1), increases autophagy in high-glucose-induced cardiomyocyte injury. We constructed a hyperglycemia model with cultured cardiomyocytes from neonatal rats. Highglucose- induced inhibition of autophagy and cardiomyocyte injury were attenuated by Bmal1 overexpression and aggravated by its knockdown. Furthermore, autophagy stabilization by 3-methyladenine or rapamycin partially suppressed the effects of altered Bmal1 expression on cardiomyocyte survival. Mechanistically, Bmal1 mediated resistance to high-glucose-induced inhibition of autophagy at least partly by inhibiting mTOR signaling activity. Collectively, our findings suggest that the clock gene Bmal1 is a positive regulator of autophagy through the mTOR signaling pathway and protects cardiomyocytes against high-glucose toxicity.
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