Cardiac progenitor cell cycling stimulated by pim-1 kinase

Circ Res. 2010 Mar 19;106(5):891-901. doi: 10.1161/CIRCRESAHA.109.208629. Epub 2010 Jan 14.

Abstract

Rationale: Cardioprotective effects of Pim-1 kinase have been previously reported but the underlying mechanistic basis may involve a combination of cellular and molecular mechanisms that remain unresolved. The elucidation of the mechanistic basis for Pim-1 mediated cardioprotection provides important insights for designing therapeutic interventional strategies to treat heart disease.

Objective: Effects of cardiac-specific Pim-1 kinase expression on the cardiac progenitor cell (CPC) population were examined to determine whether Pim-1 mediates beneficial effects through augmenting CPC activity.

Methods and results: Transgenic mice created with cardiac-specific Pim-1 overexpression (Pim-wt) exhibit enhanced Pim-1 expression in both cardiomyocytes and CPCs, both of which show increased proliferative activity assessed using 5-bromodeoxyuridine (BrdU), Ki-67, and c-Myc relative to nontransgenic controls. However, the total number of CPCs was not increased in the Pim-wt hearts during normal postnatal growth or after infarction challenge. These results suggest that Pim-1 overexpression leads to asymmetric division resulting in maintenance of the CPC population. Localization and quantitation of cell fate determinants Numb and alpha-adaptin by confocal microscopy were used to assess frequency of asymmetric division in the CPC population. Polarization of Numb in mitotic phospho-histone positive cells demonstrates asymmetric division in 65% of the CPC population in hearts of Pim-wt mice versus 26% in nontransgenic hearts after infarction challenge. Similarly, Pim-wt hearts had fewer cells with uniform alpha-adaptin staining indicative of symmetrically dividing CPCs, with 36% of the CPCs versus 73% in nontransgenic sections.

Conclusions: These findings define a mechanistic basis for enhanced myocardial regeneration in transgenic mice overexpressing Pim-1 kinase.

Publication types

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

MeSH terms

  • Adaptor Protein Complex alpha Subunits / metabolism
  • Animals
  • Cell Cycle*
  • Cell Proliferation*
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Histones / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Mutation
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / pathology
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Regeneration*
  • Stem Cells / enzymology*
  • Stem Cells / pathology
  • Time Factors

Substances

  • Adaptor Protein Complex alpha Subunits
  • Histones
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Numb protein, mouse
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1