Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury

Satoru Kobayashi, Xianmin Xu, Kai Chen, Qiangrong Liang

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Hyperglycemia is linked to increased heart failure among diabetic patients. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Autophagy is a cellular degradation pathway that plays important roles in cellular homeostasis. Autophagic activity is altered in the diabetic heart, but its functional role has been unclear. In this study, we determined if mimicking hyperglycemia in cultured cardiomyocytes from neonatal rats and adult mice could affect autophagic activity and myocyte viability. High glucose (17 or 30 mM) reduced autophagic flux compared with normal glucose (5.5 mM) as indicated by the difference in protein levels of LC3-II (microtubule-associated protein 1 light chain 3 form II) or the changes of punctate fluorescence patterns of GFP-LC3 and mRFP-LC3 in the absence and presence of the lysosomal inhibitor bafilomycin A1. Unexpectedly, the inhibited autophagy turned out to be an adaptive response that functioned to limit high glucose cardiotoxicity. Indeed, suppression of autophagy by 3-methyladenine or short hairpin RNA-mediated silencing of the Becn1 or Atg7 gene attenuated high glucose-induced cardiomyocyte death. Conversely, upregulation of autophagy with rapamycin or overexpression of Becn1 or Atg7 predisposed cardiomyocytes to high glucose toxicity. Mechanistically, the high glucose-induced inhibition of autophagy was mediated at least partly by increased mTOR signaling that likely inactivated ULK1 through phosphorylation at serine 467. Together, these findings demonstrate that high glucose inhibits autophagy, which is a beneficial adaptive response that protects cardiomyocytes against high glucose toxicity. Future studies are warranted to determine if autophagy plays a similar role in diabetic heart in vivo.

Original languageEnglish (US)
Pages (from-to)577-592
Number of pages16
JournalAutophagy
Volume8
Issue number4
DOIs
StatePublished - Jan 1 2012

Fingerprint

Autophagy
Cardiac Myocytes
Glucose
Wounds and Injuries
Hyperglycemia
Microtubule-Associated Proteins
Sirolimus
RNA Interference
Muscle Cells
Serine
Small Interfering RNA
Homeostasis
Up-Regulation
Heart Failure
Fluorescence
Phosphorylation
Light
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. / Kobayashi, Satoru; Xu, Xianmin; Chen, Kai; Liang, Qiangrong.

In: Autophagy, Vol. 8, No. 4, 01.01.2012, p. 577-592.

Research output: Contribution to journalArticle

Kobayashi, Satoru ; Xu, Xianmin ; Chen, Kai ; Liang, Qiangrong. / Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. In: Autophagy. 2012 ; Vol. 8, No. 4. pp. 577-592.
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