Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair.
Heart disease is a leading cause of death in newborn children and in adults. Efforts to promote cardiac repair through the use of stem cells hold promise but typically involve isolation and introduction of progenitor cells. Here, we show that the G-actin sequestering peptide thymosin beta4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta4. We found that thymosin beta4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt (also known as protein kinase B). After coronary artery ligation in mice, thymosin beta4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival and improved cardiac function. These findings suggest that thymosin beta4 promotes cardiomyocyte migration, survival and repair and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage.
Bock-Marquette
Ildiko
I
Department of Pediatrics, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, Texas 75390-9148, USA.
Saxena
Ankur
A
White
Michael D
MD
Dimaio
J Michael
JM
Srivastava
Deepak
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002465:Cell Movement; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000502:physiology; D060588:LIM Domain Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012038:Regeneration / Q000502:physiology*; D013947:Thymosin / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013947:Thymosin; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK; C490232:Lims1 protein, mouse