title: C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.
abstract: BACKGROUND
  The regenerative capacity of the heart is markedly diminished shortly after birth, coinciding with overall withdrawal of cardiomyocytes from cell cycle. Consequently, the adult mammalian heart has limited capacity to regenerate after injury. The discovery of factors that can induce cardiomyocyte proliferation is, therefore, of high interest and has been the focus of extensive investigation throughout the past years.
  
  
  OBJECTIVE
  We have recently identified C3orf58 as a novel hypoxia and Akt induced stem cell factor (HASF) secreted from mesenchymal stem cells, which can promote cardiac repair through cytoprotective mechanisms. Here, we tested the hypothesis that HASF can also contribute to cardiac regeneration by stimulating cardiomyocyte division and proliferation.
  
  
  RESULTS
  Neonatal ventricular cardiomyocytes were stimulated in culture for 7 days with purified recombinant HASF protein. Compared with control untreated cells, HASF-treated neonatal cardiomyocytes exhibited 60% increase in DNA synthesis as measured by bromodeoxyuridine incorporation. These results were confirmed by immunofluorescence confocal microscopy showing a 50% to 100% increase in the number of cardiomyocytes in the mitotic and cytokinesis phases. Importantly, in vivo cardiac overexpression of HASF in a transgenic mouse model resulted in enhanced level of DNA synthesis and cytokinesis in neonatal and adult cardiomyocytes. These proliferative effects were modulated by a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway as revealed by the use of phosphoinositide 3-kinase -pathway-specific inhibitors and silencing of the Cdk7 gene.
  
  
  CONCLUSIONS
  Our studies support the hypothesis that HASF induces cardiomyocyte proliferation via a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway. The implications of this finding may be significant for cardiac regeneration biology and therapeutics.
authors.affiliation: Department of Medicine, Mandel Center for Hypertension and Atherosclerosis Research, Cardiovascular Research Center, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Farideh
authors.initials: F
authors.lastname: Beigi
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schmeckpeper
authors.forename: Pete
authors.initials: P
authors.lastname: Pow-Anpongkul
authors.forename: James Alan
authors.initials: JA
authors.lastname: Payne
authors.forename: Lunan
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C532314:DIPK2A protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase
keywords: myocytes, cardiac; paracrine; proliferation; regeneration