title: SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: pressure-related effects.
abstract: BACKGROUND
  Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart.
  
  
  METHODS
  Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 μM); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies.
  
  
  RESULTS
  An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (ψm) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption of ψm and exacerbated cell death; these effects were greater at low pressure.
  
  
  CONCLUSIONS
  The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart.
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Jun Yao
authors.initials: JY
authors.lastname: Liu
authors.forename: Mahmood S
authors.initials: MS
authors.lastname: Mozaffari
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure; D004789:Enzyme Activation; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D064094:Interleukin-27 / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D053078:Membrane Potential, Mitochondrial; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D009336:Necrosis; D010477:Perfusion; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D018836:Inflammation Mediators; D016753:Interleukin-10; D020381:Interleukin-17; D064094:Interleukin-27; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051742:Transcription Factor CHOP; D000099184:Serum-Glucocorticoid Regulated Kinases; C497251:Ddit3 protein, rat; C515934:Il17a protein, rat
keywords: GADD153; SGK-1.; blood pressure; cell death; heart; hypertension; inflammation; ischemia reperfusion; pressure overload