title: Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury.
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 A(1). 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.
authors.affiliation: Cardiovascular Health Research Center, Sanford Research/ University of South Dakota, Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Xianmin
authors.initials: X
authors.lastname: Xu
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Liang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D002316:Cardiotonic Agents / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
chemical_list: C561242:Atg7 protein, rat; D002316:Cardiotonic Agents; D051638:Ether-A-Go-Go Potassium Channels; C496887:Kcnh3 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; C025946:3-methyladenine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D005947:Glucose; D000225:Adenine; D020123:Sirolimus