Thymosin β4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection

Rabea Hinkel, Chiraz El-Aouni, Tonia Olson, Jan Horstkotte, Stefan Mayer, Sebastian Müller, Michael Willhauck, Christine Spitzweg, Franz Josef Gildehaus, Wolfgang Münzing, Ewald Hannappel, Ildiko Bock-Marquette, J. Michael DiMaio, Antonis K. Hatzopoulos, Peter Boekstegers, Christian Kupatt

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

Background-Prolonged myocardial ischemia results in cardiomyocyte loss despite successful revascularization. We have reported that retrograde application of embryonic endothelial progenitor cells (eEPCs) provides rapid paracrine protection against ischemia-reperfusion injury. Here, we investigated the role of thymosin β4 (Tβ4) as a mediator of eEPC-mediated cardioprotection. Methods and Results-In vitro, neonatal rat cardiomyocytes were subjected to hypoxia-reoxygenation in the absence or presence of eEPCs with or without Tβ4 short hairpin RNA (shRNA) transfection. In vivo, pigs (n=9 per group) underwent percutaneous left anterior descending artery occlusion for 60 minutes on day 1. After 55 minutes of ischemia, control eEPCs (5×10 6 cells) or cells transfected with Tβ4 shRNA when indicated or 15 mg Tβ4 alone were retroinfused into the anterior interventricular vein. Segmental endocardial shortening in the infarct zone at 150-bpm atrial pacing, infarct size (triphenyl tetrazolium chloride viability and methylene blue exclusion), and inflammatory cell influx (myeloperoxidase activity) were determined 24 hours later. Survival of neonatal rat cardiomyocytes increased from 32±4% to 90±2% after eEPC application, an effect sensitive to shRNA transfection compared with Tβ4 (45±7%). In vivo, infarct size decreased with eEPC application (38±4% versus 54±4% of area at risk; P<0.01), an effect abolished by Tβ4 shRNA (62±3%). Segmental subendocardial shortening improved after eEPC treatment (22±3% versus -3±4% of control area) unless T-4 shRNA was transfected (-6±4%). Retroinfusion of Tβ4 mimicked eEPC application (infarct size, 37±3%; segmental endocardial shortening, 34±7%). Myeloperoxidase activity (3323±388 U/mg in controls) was decreased by eEPCs (1996±546 U/mg) or Tβ4 alone (1455±197 U/mg) but not Tβ4 shRNA-treated eEPCs (5449±829 U/mg). Conclusion-Our findings show that short-term cardioprotection derived by regional application of eEPCs can be attributed, at least in part, to Tβ4. (Circulation. 2008;117:2232-2240.)

Original languageEnglish (US)
Pages (from-to)2232-2240
Number of pages9
JournalCirculation
Volume117
Issue number17
DOIs
StatePublished - Apr 29 2008

Keywords

  • Ischemia
  • Molecular biology
  • Myocardial infarction
  • Progenitor cells
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Hinkel, R., El-Aouni, C., Olson, T., Horstkotte, J., Mayer, S., Müller, S., Willhauck, M., Spitzweg, C., Gildehaus, F. J., Münzing, W., Hannappel, E., Bock-Marquette, I., DiMaio, J. M., Hatzopoulos, A. K., Boekstegers, P., & Kupatt, C. (2008). Thymosin β4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection. Circulation, 117(17), 2232-2240. https://doi.org/10.1161/CIRCULATIONAHA.107.758904