Pim-1 kinase protects mitochondrial integrity in cardiomyocytes

Circ Res. 2010 Apr 16;106(7):1265-74. doi: 10.1161/CIRCRESAHA.109.212035. Epub 2010 Mar 4.

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-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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Disease Models, Animal
  • Humans
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Transgenic
  • Mitochondria, Heart / enzymology*
  • Mitochondria, Heart / ultrastructure
  • Mitochondrial Swelling
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / ultrastructure
  • Oxidative Stress
  • Protein Transport
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / metabolism
  • Time Factors
  • Transfection
  • bcl-X Protein / metabolism

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Bcl2l1 protein, mouse
  • Bid protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-X Protein
  • Cytochromes c
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1