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C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.

Publication ,  Journal Article
Beigi, F; Schmeckpeper, J; Pow-Anpongkul, P; Payne, JA; Zhang, L; Zhang, Z; Huang, J; Mirotsou, M; Dzau, VJ
Published in: Circ Res
August 2, 2013

RATIONALE: 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. METHODS AND 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.

Duke Scholars

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

August 2, 2013

Volume

113

Issue

4

Start / End Page

372 / 380

Location

United States

Related Subject Headings

  • Signal Transduction
  • Regeneration
  • Recombinant Proteins
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • Myocytes, Cardiac
  • Models, Animal
  • Mice, Transgenic
  • Mice
 

Citation

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Beigi, F., Schmeckpeper, J., Pow-Anpongkul, P., Payne, J. A., Zhang, L., Zhang, Z., … Dzau, V. J. (2013). C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ Res, 113(4), 372–380. https://doi.org/10.1161/CIRCRESAHA.113.301075
Beigi, Farideh, Jeffrey Schmeckpeper, Pete Pow-Anpongkul, James Alan Payne, Lunan Zhang, Zhiping Zhang, Jing Huang, Maria Mirotsou, and Victor J. Dzau. “C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.Circ Res 113, no. 4 (August 2, 2013): 372–80. https://doi.org/10.1161/CIRCRESAHA.113.301075.
Beigi F, Schmeckpeper J, Pow-Anpongkul P, Payne JA, Zhang L, Zhang Z, et al. C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ Res. 2013 Aug 2;113(4):372–80.
Beigi, Farideh, et al. “C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.Circ Res, vol. 113, no. 4, Aug. 2013, pp. 372–80. Pubmed, doi:10.1161/CIRCRESAHA.113.301075.
Beigi F, Schmeckpeper J, Pow-Anpongkul P, Payne JA, Zhang L, Zhang Z, Huang J, Mirotsou M, Dzau VJ. C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ Res. 2013 Aug 2;113(4):372–380.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

August 2, 2013

Volume

113

Issue

4

Start / End Page

372 / 380

Location

United States

Related Subject Headings

  • Signal Transduction
  • Regeneration
  • Recombinant Proteins
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • Myocytes, Cardiac
  • Models, Animal
  • Mice, Transgenic
  • Mice