title: Local delivery of a PKCε-activating peptide limits ischemia reperfusion injury in the aged female rat heart.
abstract: Reduced efficacy of cardioprotective interventions in the aged female heart, including estrogen replacement, highlights the need for alternative therapeutics to reduce myocardial ischemia-reperfusion (I/R) injury in postmenopausal women. Here, we sought to determine the efficacy of protein kinase-Cε (PKCε)-mediated cardioprotection in the aged, estradiol-deficient rat heart. Infarct size and functional recovery were assessed in Langendorff-perfused hearts from adult (5 mo) or aged (23 mo) female Fisher 344 ovary-intact or ovariectomized (OVX) rats administered a PKCε-activator, receptor for activated C kinase (ψεRACK) prior to 47-min ischemia and 60-min reperfusion. Proteomic analysis was conducted on left ventricular mitochondrial fractions treated with ψεRACK prior to I/R, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) 8plex labeling and tandem mass spectrometry. Real-time PCR was utilized to assess connexin 43 (Cx43) and RACK2 mRNA post-I/R. Greater infarct size in aged OVX (78%) vs. adult (37%) was reduced by ψεRACK (35%, P < 0.0001) and associated with greater mitochondrial PKCε localization (P < 0.0003). Proteomic analysis revealed three novel mitochondrial targets of PKCε-mediated cardioprotection with aging (P < 0.05): the antioxidant enzymes glutathione peroxidase (GPX) and MnSOD2, and heat shock protein 10. Finally, decreased levels of Cx43 and RACK2 mRNA seen with age were partially abrogated by administration of ψεRACK (P < 0.05). The mechanisms described here may represent important therapeutic candidates for the treatment of acute myocardial infarction in postmenopausal women and age-associated estradiol deficiency.
authors: Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors: T S
authors: TS
authors: Lancaster
authors: S J
authors: SJ
authors: Jefferson
authors: D H
authors: DH
authors: Korzick
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D018835:Chaperonin 10 / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004958:Estradiol / Q000172:deficiency; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage*; D010052:Ovariectomy; D010477:Perfusion; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D020127:Recovery of Function; D013482:Superoxide Dismutase / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D000099156:Superoxide Dismutase 2
chemical_list: D002316:Cardiotonic Agents; D018835:Chaperonin 10; D018031:Connexin 43; D004958:Estradiol; D005979:Glutathione Peroxidase; D008565:Membrane Proteins; D009842:Oligopeptides; D051744:Protein Kinase C-epsilon; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C543179:Copb1 protein, rat; C477271:His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp; C497257:Prkce protein, rat