title: Interleukin-10 inhibits chronic angiotensin II-induced pathological autophagy.
abstract: BACKGROUND
  Although autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is unknown. Here we tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, leads to improve cardiac function.
  
  
  RESULTS
  Chronic Ang II strongly induced mortality, cardiac dysfunction in IL-10 Knockout mice. IL-10 deletion exaggerated pathological autophagy in response to Ang II treatment. In isolated cardiac myocytes, IL-10 attenuated Ang II-induced pathological autophagy and activated Akt/mTORC1 signaling. Pharmacological or molecular inhibition of Akt and mTORC1 signaling attenuated IL-10 effects on Ang II-induced pathological autophagy. Furthermore, lysosomal inhibition in autophagic flux experiments further confirmed that IL-10 inhibits pathological autophagy via mTORC1 signaling.
  
  
  CONCLUSIONS
  Our data demonstrate a novel role of IL-10 in regulation of pathological autophagy; thus can act as a potential therapeutic molecule for treatment of chronic heart disease.
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA; Department of Pharmacology, Temple University, Philadelphia 19140, USA. Electronic address: raj.kishore@temple.edu.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Department of Cardiovascular Science, Houston Methodist Research Institute, Houston 77030, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA.
authors.forename: Venkata Naga Srikanth
authors.initials: VN
authors.lastname: Garikipati
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Benedict
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Nickoloff
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gumpert
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA; Department of Pharmacology, Temple University, Philadelphia 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia 19140, USA. Electronic address: suresh.verma@temple.edu.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Verma
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D006332:Cardiomegaly / Q000150:complications / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D006333:Heart Failure / Q000150:complications / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology / Q000648:ultrastructure; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D016753:Interleukin-10; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D058570:TOR Serine-Threonine Kinases; C115010:Becn1 protein, mouse
keywords: Autophagy; Cardiomyocytes; PI3K/Akt signaling; Signaling; mTORC1