title: Cardiac progenitor cell cycling stimulated by pim-1 kinase.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: San Diego State Heart Institute, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Cottage
authors.forename: Brandi
authors.initials: B
authors.lastname: Bailey
authors.forename: Kimberlee M
authors.initials: KM
authors.lastname: Fischer
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitable
authors.forename: Brett
authors.initials: B
authors.lastname: Collins
authors.forename: Savilla
authors.initials: S
authors.lastname: Tuck
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.forename: John
authors.initials: J
authors.lastname: Muraski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D033965:Adaptor Protein Complex alpha Subunits / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
chemical_list: D033965:Adaptor Protein Complex alpha Subunits; D006657:Histones; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1