title: Pim-1 kinase protects mitochondrial integrity in cardiomyocytes.
abstract: BACKGROUND
  Cardioprotective signaling mediates antiapoptotic actions through multiple mechanisms including maintenance of mitochondrial integrity. Pim-1 kinase is an essential downstream effector of AKT-mediated cardioprotection but the mechanistic basis for maintenance of mitochondrial integrity by Pim-1 remains unexplored. This study details antiapoptotic actions responsible for enhanced cell survival in cardiomyocytes with elevated Pim-1 activity.
  
  
  OBJECTIVE
  The purpose of this study is to demonstrate that the cardioprotective kinase Pim-1 acts to inhibit cell death by preserving mitochondrial integrity in cardiomyocytes.
  
  
  RESULTS
  A combination of biochemical, molecular, and microscopic analyses demonstrate beneficial effects of Pim-1 on mitochondrial integrity. Pim-1 protein level increases in the mitochondrial fraction with a corresponding decrease in the cytosolic fraction of myocardial lysates from hearts subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Cardiac-specific overexpression of Pim-1 results in higher levels of antiapoptotic Bcl-X(L) and Bcl-2 compared to samples from normal hearts. In response to oxidative stress challenge, Pim-1 preserves the inner mitochondrial membrane potential. Ultrastructure of the mitochondria is maintained by Pim-1 activity, which prevents swelling induced by calcium overload. Finally, mitochondria isolated from hearts created with cardiac-specific overexpression of Pim-1 show inhibition of cytochrome c release triggered by a truncated form of proapoptotic Bid.
  
  
  CONCLUSIONS
  Cardioprotective action of Pim-1 kinase includes preservation of mitochondrial integrity during cardiomyopathic challenge conditions, thereby raising the potential for Pim-1 kinase activation as a therapeutic interventional approach to inhibit cell death by antagonizing proapoptotic Bcl-2 family members that regulate the intrinsic apoptotic pathway.
authors.affiliation: San Diego State Heart Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Gwynngelle A
authors.initials: GA
authors.lastname: Borillo
authors.forename: Matt
authors.initials: M
authors.lastname: Mason
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Christopher
authors.initials: C
authors.lastname: Cottage
authors.forename: Michael
authors.initials: M
authors.lastname: McGregor
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.forename: Kimberlee
authors.initials: K
authors.lastname: Fischer
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Steven
authors.initials: S
authors.lastname: Barlow
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.forename: Silvia
authors.initials: S
authors.lastname: Truffa
authors.forename: Ross
authors.initials: R
authors.lastname: Whittaker
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Glassy
authors.forename: Asa B
authors.initials: AB
authors.lastname: Gustafsson
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Glembotski
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000648:ultrastructure; D008933:Mitochondrial Swelling; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000648:ultrastructure; D018384:Oxidative Stress; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494812:Bcl2l1 protein, mouse; C494815:Bid protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D045304:Cytochromes c; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1