title: Pressure overload regulates expression of cytokines, γH2AX, and growth arrest- and DNA-damage inducible protein 153 via glycogen synthase kinase-3β in ischemic-reperfused hearts.
abstract: The growth arrest- and DNA-damage inducible protein 153 (GADD153) regulates both apoptosis and inflammatory response. Importantly, glycogen synthase kinase-3β (GSK-3β) may provide a mechanistic link for cellular expression of GADD153, inflammatory response, and cell death. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion injury associated with significant reduction in phosphorylated (inactive) GSK-3β. This raises the possibility that pressure overload, through a GSK-3β-dependent mechanism, increases GADD153 expression, thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial ischemia reperfusion injury. Accordingly, Langendorff-perfused rat hearts were subjected to global ischemia reperfusion protocol in the absence or presence of the GSK-3β inhibitor, lithium chloride (1 mmol/L), with perfusion pressure set at 80 or 160 cmH(2)O; normoxic hearts served as controls. Compared with normoxia, an ischemia reperfusion insult increased expressions of proinflammatory cytokines, γH2AX, and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload did the following: (1) reduced interleukin-10 but increased interleukin-17 (cardiomyocytes), without affecting interleukin-23; (2) increased expressions of γH2AX and GADD153; (3) decreased 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) aggregates but increased JC-1 monomers (suggestive of reduced mitochondrial membrane potential, ψ(m)); and (4) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Treatment with lithium chloride caused a robust increase in interleukin-10, preserved ψ(m), and markedly decreased all other parameters with the effect being most prominent for hearts perfused at the high pressure. In conclusion, pressure overload, via a GSK-3β-dependent mechanism, exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of inflammatory response, DNA injury, and GADD153 expression.
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Health Sciences University, Augusta, GA 30912, USA. bbaban@georgiahealth.edu
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; D016207:Cytokines / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006657:Histones / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion / Q000379:methods; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: D016207:Cytokines; D006657:Histones; D010750:Phosphoproteins; C577575:gamma-H2AX protein, rat; D051742:Transcription Factor CHOP; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride