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(Circulation. 2008;117:2232-2240.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Thymosin β4 Is an Essential Paracrine Factor of Embryonic Endothelial Progenitor Cell–Mediated Cardioprotection

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

From Medizinische Klinik I (R.H., C.E.-A., T.O., J.H., S. Mayer, S. Müller, P.B., C.K.), Internal Medicine II (M.W., C.S., E.H.), and Department of Nuclear Medicine (F.G., W.M.), University Clinic Grosshadern, Munich, Germany; Institute for Biochemistry (M.W., C.S., E.H.), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; Department of Cardiovascular and Thoracic Surgery (I.B.-M., J.M.D.), University of Texas Southwestern Medical Center, Dallas; and Department of Medicine, Division of Cardiovascular Medicine and Department of Cell and Developmental Biology (A.K.H.), Vanderbilt University, Nashville, Tenn.

Correspondence to Christian Kupatt, University of Munich, Medizinische Klinik I, Klinikum Großhadern, Universität München, Marchioninistrasse 15, Munchen, Germany D-81377. E-mail christian.kupatt{at}med.uni-muenchen.de

Received August 2, 2007; accepted February 21, 2008.

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 (5x10⁶ 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 Tβ4 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.

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Clinical Summaries
Circulation 2008 117: 2169. [Full Text]