C3orf58 , a Novel Paracrine Protein, Stimulates Cardiomyocyte Cell-Cycle Progression Through the PI3K–AKT–CDK7 Pathway
| Autor: | Pete Pow-anpongkul, James Alan Payne, Maria Mirotsou, Victor J. Dzau, Zhiping Zhang, Jeffrey Schmeckpeper, Lunan Zhang, Farideh Beigi, Jing Huang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Physiology
Mice Transgenic Stem cell factor In Vitro Techniques Biology Article Mice Phosphatidylinositol 3-Kinases Paracrine signalling Cyclin-dependent kinase Animals Humans Regeneration Myocytes Cardiac Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Cell Proliferation Cell growth Cell Cycle Membrane Proteins Heart DNA Cell cycle Cyclin-Dependent Kinases Recombinant Proteins Rats Cell biology Adaptor Proteins Vesicular Transport Models Animal biology.protein Intercellular Signaling Peptides and Proteins Cyclin-dependent kinase 7 Cardiology and Cardiovascular Medicine Proto-Oncogene Proteins c-akt Cyclin-Dependent Kinase-Activating Kinase Signal Transduction |
| Zdroj: | Circulation Research. 113:372-380 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.113.301075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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