Pim-1 kinase protects mitochondrial integrity in cardiomyocytes

Gwynngelle A. Borillo, Matt Mason, Pearl Quijada, Mirko Völkers, Christopher Cottage, Michael McGregor, Shabana Din, Kimberlee Fischer, Natalie Gude, Daniele Avitabile, Steven Barlow, Roberto Alvarez, Silvia Truffa, Ross Whittaker, Matthew S. Glassy, Asa B. Gustafsson, Shigeki Miyamoto, Christopher C. Glembotski, Roberta A. Gottlieb, Joan Heller BrownMark A. Sussman

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1265-1274
Number of pages10
JournalCirculation research
Volume106
Issue number7
DOIs
StatePublished - Apr 2010
Externally publishedYes

Keywords

  • Apoptosis
  • Cardiomyocyte
  • Mitochondria
  • Pim-1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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