TY - JOUR
T1 - Pim-1 kinase protects mitochondrial integrity in cardiomyocytes
AU - Borillo, Gwynngelle A.
AU - Mason, Matt
AU - Quijada, Pearl
AU - Völkers, Mirko
AU - Cottage, Christopher
AU - McGregor, Michael
AU - Din, Shabana
AU - Fischer, Kimberlee
AU - Gude, Natalie
AU - Avitabile, Daniele
AU - Barlow, Steven
AU - Alvarez, Roberto
AU - Truffa, Silvia
AU - Whittaker, Ross
AU - Glassy, Matthew S.
AU - Gustafsson, Asa B.
AU - Miyamoto, Shigeki
AU - Glembotski, Christopher C.
AU - Gottlieb, Roberta A.
AU - Brown, Joan Heller
AU - Sussman, Mark A.
PY - 2010/4
Y1 - 2010/4
N2 - RATIONALE: 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. METHODS AND 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-XL 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. CONCLUSION: 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.
AB - RATIONALE: 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. METHODS AND 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-XL 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. CONCLUSION: 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.
KW - Apoptosis
KW - Cardiomyocyte
KW - Mitochondria
KW - Pim-1
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U2 - 10.1161/CIRCRESAHA.109.212035
DO - 10.1161/CIRCRESAHA.109.212035
M3 - Article
C2 - 20203306
AN - SCOPUS:77951299101
SN - 0009-7330
VL - 106
SP - 1265
EP - 1274
JO - Circulation research
JF - Circulation research
IS - 7
ER -