Thymosin β4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo

Ildiko Bock-Marquette, Santwana Shrivastava, G. C Teg Pipes, Jeffrey E. Thatcher, Allissa Blystone, John M. Shelton, Cristi L. Galindo, B. Melegh, Deepak Srivastava, Eric N. Olson, J. Michael DiMaio

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Hypoxic heart disease is a predominant cause of disability and death worldwide. Since adult mammalian hearts are incapable of regeneration after hypoxia, attempts to modify this deficiency are critical. As demonstrated in zebrafish, recall of the embryonic developmental program may be the key to success. Because thymosin β4 (TB4) is beneficial for myocardial cell survival and essential for coronary development in embryos, we hypothesized that it reactivates the embryonic developmental program and initiates epicardial progenitor mobilization in adult mammals. We found that TB4 stimulates capillary-like tube formation of adult coronary endothelial cells and increases embryonic endothelial cell migration and proliferation in vitro. The increase of blood vessel/epicardial substance (Bves) expressing cells accompanied by elevated VEGF, Flk-1, TGF-β, Fgfr-2, Fgfr-4, Fgf-17 and β-Catenin expression and increase of Tbx-18 and Wt-1 positive myocardial progenitors suggested organ-wide recall of the embryonic program in the adult epicardium. TB4 also positively regulated the expression and phosphorylation of myristoylated alanine-rich C-kinase substrate (Marcks), a direct substrate and indicator of protein kinase C (PKC) activity in vitro and in vivo. PKC inhibition significantly reduced TB4 initiated epicardial thickening, capillary growth and the number of myocardial progenitors. Our results demonstrate that TB4 is the first known molecule capable of organ-wide activation of the embryonic coronary developmental program in the adult mammalian heart after systemic administration and that PKC plays a significant role in the process.

Original languageEnglish
Pages (from-to)728-738
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume46
Issue number5
DOIs
Publication statusPublished - May 2009

Fingerprint

Thymosin
Protein Kinase C
Stem Cells
Endothelial Cells
Catenins
Pericardium
Zebrafish
Vascular Endothelial Growth Factor A
Embryonic Development
Cell Movement
Blood Vessels
Regeneration
Cause of Death
Mammals
Heart Diseases
Cell Survival
Phosphorylation
Cell Proliferation
Growth
In Vitro Techniques

Keywords

  • Cardiac regeneration
  • Coronary development
  • PKC
  • Progenitor cells
  • Thymosin β4

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Thymosin β4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo. / Bock-Marquette, Ildiko; Shrivastava, Santwana; Pipes, G. C Teg; Thatcher, Jeffrey E.; Blystone, Allissa; Shelton, John M.; Galindo, Cristi L.; Melegh, B.; Srivastava, Deepak; Olson, Eric N.; DiMaio, J. Michael.

In: Journal of Molecular and Cellular Cardiology, Vol. 46, No. 5, 05.2009, p. 728-738.

Research output: Contribution to journalArticle

Bock-Marquette, I, Shrivastava, S, Pipes, GCT, Thatcher, JE, Blystone, A, Shelton, JM, Galindo, CL, Melegh, B, Srivastava, D, Olson, EN & DiMaio, JM 2009, 'Thymosin β4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo', Journal of Molecular and Cellular Cardiology, vol. 46, no. 5, pp. 728-738. https://doi.org/10.1016/j.yjmcc.2009.01.017
Bock-Marquette, Ildiko ; Shrivastava, Santwana ; Pipes, G. C Teg ; Thatcher, Jeffrey E. ; Blystone, Allissa ; Shelton, John M. ; Galindo, Cristi L. ; Melegh, B. ; Srivastava, Deepak ; Olson, Eric N. ; DiMaio, J. Michael. / Thymosin β4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo. In: Journal of Molecular and Cellular Cardiology. 2009 ; Vol. 46, No. 5. pp. 728-738.
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AU - Thatcher, Jeffrey E.

AU - Blystone, Allissa

AU - Shelton, John M.

AU - Galindo, Cristi L.

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