Pim-1 kinase protects mitochondrial integrity in cardiomyocytes.
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.
Borillo
Gwynngelle A
GA
San Diego State Heart Institute, San Diego State University, San Diego, CA 92182, USA.
Mason
Matt
M
Quijada
Pearl
P
Völkers
Mirko
M
Cottage
Christopher
C
McGregor
Michael
M
Din
Shabana
S
Fischer
Kimberlee
K
Gude
Natalie
N
Avitabile
Daniele
D
Barlow
Steven
S
Alvarez
Roberto
R
Truffa
Silvia
S
Whittaker
Ross
R
Glassy
Matthew S
MS
Gustafsson
Asa B
AB
Miyamoto
Shigeki
S
Glembotski
Christopher C
CC
Gottlieb
Roberta A
RA
Brown
Joan Heller
JH
Sussman
Mark A
MA
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
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