title: Autophagy protects against senescence and apoptosis via the RAS-mitochondria in high-glucose-induced endothelial cells.
abstract: BACKGROUND
  Autophagy is an important process in the pathogenesis of diabetes and plays a critical role in maintaining cellular homeostasis. However, the autophagic response and its mechanism in diabetic vascular endothelium remain unclear.
  
  
  RESULTS
  We studied high-glucose-induced renin-angiotensin system (RAS)-mitochondrial damage and its effect on endothelial cells. With regard to therapeutics, we investigated the beneficial effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) against high-glucose-induced endothelial responses. High glucose activated RAS, enhanced mitochondrial damage and increased senescence, apoptosis and autophagic-responses in endothelial cells, and these effects were mimicked by using angiotensin II (Ang). The use of an ACEI or ARB, however, inhibited the negative effects of high glucose. Direct mitochondrial injury caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) resulted in similar negative effects of high glucose or Ang and abrogated the protective effects of an ACEI or ARB. Additionally, by impairing autophagy, high-glucose-induced senescence and apoptosis were accelerated and the ACEI- or ARB-mediated beneficial effects were abolished. Furthermore, increases in FragEL™ DNA Fragmentation (TUNEL)-positive cells, β-galactosidase activation and the expression of autophagic biomarkers were revealed in diabetic patients and rats, and the treatment with an ACEI or ARB decreased these responses.
  
  
  CONCLUSIONS
  These data suggest that autophagy protects against senescence and apoptosis via RAS-mitochondria in high-glucose-induced endothelial cells.
authors.affiliation: Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Fen-Qiang
authors.initials: FQ
authors.lastname: Xiao
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Wu
authors.forename: Ri-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Ze-Wei
authors.initials: ZW
authors.lastname: Sun
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Fu
authors.forename: Yun
authors.initials: Y
authors.lastname: Mou
authors.forename: Wu
authors.initials: W
authors.lastname: Tao
authors.forename: Xiao-Sheng
authors.initials: XS
authors.lastname: Hu
authors.forename: Shen-Jiang
authors.initials: SJ
authors.lastname: Hu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D016922:Cellular Senescence / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D006835:Hydrazones; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C070053:carbonyl 3-chlorophenylhydrazone; D001616:beta-Galactosidase; D005947:Glucose