Thymosin beta4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo.
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 beta4 (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-beta, Fgfr-2, Fgfr-4, Fgf-17 and beta-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.
Bock-Marquette
Ildiko
I
Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-9148, USA. Ildiko.Bock-Marquette@UTSouthwestern.edu
Shrivastava
Santwana
S
Pipes
G C Teg
GC
Thatcher
Jeffrey E
JE
Blystone
Allissa
A
Shelton
John M
JM
Galindo
Cristi L
CL
Melegh
Bela
B
Srivastava
Deepak
D
Olson
Eric N
EN
DiMaio
J Michael
JM
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006321:Heart / Q000196:embryology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010496:Pericardium / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D013947:Thymosin / Q000378:metabolism* / Q000494:pharmacology; D000099201:Thymosin beta(4)
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C; D013947:Thymosin; D000099201:Thymosin beta(4); C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; C000619712:Marcks protein, rat