title: Chronic Akt activation attenuated lipopolysaccharide-induced cardiac dysfunction via Akt/GSK3β-dependent inhibition of apoptosis and ER stress.
abstract: Sepsis is characterized by systematic inflammation and contributes to cardiac dysfunction. This study was designed to examine the effect of protein kinase B (Akt) activation on lipopolysaccharide-induced cardiac anomalies and underlying mechanism(s) involved. Mechanical and intracellular Ca²⁺ properties were examined in myocardium from wild-type and transgenic mice with cardiac-specific chronic Akt overexpression following LPS (4 mg/kg, i.p.) challenge. Akt signaling cascade (Akt, phosphatase and tensin homologue deleted on chromosome ten, glycogen synthase kinase 3 beta), stress signal (extracellular-signal-regulated kinases, c-Jun N-terminal kinases, p38), apoptotic markers (Bcl-2 associated X protein, caspase-3/-9), endoplasmic reticulum (ER) stress markers (glucose-regulated protein 78, growth arrest and DNA damage induced gene-153, eukaryotic initiation factor 2α), inflammatory markers (tumor necrosis factor α, interleukin-1β, interleukin-6) and autophagic markers (Beclin-1, light chain 3B, autophagy-related gene 7 and sequestosome 1) were evaluated. Our results revealed that LPS induced marked decrease in ejection fraction, fractional shortening, cardiomyocyte contractile capacity with dampened intracellular Ca²⁺ release and clearance, elevated reactive oxygen species (ROS) generation and decreased glutathione and glutathione disulfide (GSH/GSSG) ratio, increased ERK, JNK, p38, GRP78, Gadd153, eIF2α, BAX, caspase-3 and -9, downregulated B cell lymphoma 2 (Bcl-2), the effects of which were significantly attenuated or obliterated by Akt activation. Akt activation itself did not affect cardiac contractile and intracellular Ca²⁺ properties, ROS production, oxidative stress, apoptosis and ER stress. In addition, LPS upregulated levels of Beclin-1, LC3B and Atg7, while suppressing p62 accumulation. Akt activation did not affect Beclin-1, LC3B, Atg7 and p62 in the presence or absence of LPS. Akt overexpression promoted phosphorylation of Akt and GSK3β. In vitro study using the GSK3β inhibitor SB216763 mimicked the response elicited by chronic Akt activation. Taken together, these data showed that Akt activation ameliorated LPS-induced cardiac contractile and intracellular Ca²⁺ anomalies through inhibition of apoptosis and ER stress, possibly involving an Akt/GSK3β-dependent mechanism.
authors.affiliation: Department of Burn and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, PR China.
authors.forename: Maolong
authors.initials: M
authors.lastname: Dong
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.forename: Machender R
authors.initials: MR
authors.lastname: Kandadi
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.forename: Shasha
authors.initials: S
authors.lastname: Jiang
authors.forename: Sreejayan
authors.initials: S
authors.lastname: Nair
authors.forename: Dahai
authors.initials: D
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D053453:Caspase 9 / Q000096:biosynthesis / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D009200:Myocardial Contraction / Q000187:drug effects* / Q000235:genetics; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C502661:Atg7 protein, mouse; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C490981:Gtf2h1 protein, mouse; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051742:Transcription Factor CHOP; D051758:Transcription Factor TFIIH; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D000071193:Autophagy-Related Protein 7; D002118:Calcium