PDGF-BB protects cardiomyocytes from apoptosis and improves contractile function of engineered heart tissue

Vantler, Marius; Karikkineth, Bijoy Chandapillai; Naito, Hiroshi; Tiburcy, Malte; Didié, Michael; Nose, Monika; Rosenkranz, Stephan; Zimmermann, Wolfram-H.

doi:10.1016/j.yjmcc.2010.03.008

« Previous Next »Journal of Molecular and Cellular Cardiology
Volume 48, Issue 6 , Pages 1316-1323, June 2010

PDGF-BB protects cardiomyocytes from apoptosis and improves contractile function of engineered heart tissue

Marius Vantler
- Klinik III für Innere Medizin, Universität zu Köln, Germany
- Center for Molecular Medicine (CMMC), Universität zu Köln, Germany
- These authors contributed equally.
Bijoy Chandapillai Karikkineth
- Institute for Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- These authors contributed equally.
Hiroshi Naito
- Institute for Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- These authors contributed equally.
Malte Tiburcy
- Institute for Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pharmacology, Heart Research Center Göttingen, Georg-August-University Göttingen, Germany
Michael Didié
- Institute for Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pharmacology, Heart Research Center Göttingen, Georg-August-University Göttingen, Germany
Monika Nose
- Institute for Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Stephan Rosenkranz
- Klinik III für Innere Medizin, Universität zu Köln, Germany
- Center for Molecular Medicine (CMMC), Universität zu Köln, Germany
- Correspondimg authors. Rosenkranz is to be contacted at Klinik III für Innere Medizin, Universität zu Köln, Germany. Zimmermann, University Medical Center Goettingen, Department of Pharmacology, Robert-Koch-Str. 40, 37075 Goettingen, Germany. Tel.: +49 551 39 5781; fax: +49 551 39 5699.
Wolfram-H. Zimmermann
- Institute for Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pharmacology, Heart Research Center Göttingen, Georg-August-University Göttingen, Germany
- Correspondimg authors. Rosenkranz is to be contacted at Klinik III für Innere Medizin, Universität zu Köln, Germany. Zimmermann, University Medical Center Goettingen, Department of Pharmacology, Robert-Koch-Str. 40, 37075 Goettingen, Germany. Tel.: +49 551 39 5781; fax: +49 551 39 5699.
- Current address: School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India - 721302.

Received 13 October 2009; received in revised form 26 February 2010; accepted 15 March 2010. published online 22 March 2010.

Abstract

Platelet-derived-growth-factor-BB (PDGF-BB) can protect various cell types from apoptotic cell death, and induce hypertrophic growth and proliferation, but little is known about its direct or indirect effects on cardiomyocytes. Cardiac muscle engineering is compromised by a particularly high rate of cardiomyocyte death. Here we hypothesized that PDGF-BB stimulation can (1) protect cardiomyocytes from apoptosis, (2) enhance myocyte content in and (3) consequently optimize contractile performance of engineered heart tissue (EHT). We investigated the effects of PDGF-receptor activation in neonatal rat heart monolayer- and EHT-cultures by isometric contraction experiments, cytomorphometry, ³H-thymidine and ³H-phenylalanine incorporation assays, quantitative PCR (calsequestrin 2, α-cardiac and skeletal actin, atrial natriuretic factor, α- and β-myosin heavy chain), immunoblotting (activated caspase 3, Akt-phosphorylation), and ELISA (cell death detection). PDGF-BB did not induce hypertrophy or proliferation in cardiomyocytes, but enhanced contractile performance of EHT. This effect was concentration-dependent (E_max 10ng/ml) and maximal only after transient PDGF-BB stimulation (culture days 0–7; total culture duration: 12days). Improvement of contractile function was associated with higher cardiomyocyte content, as a consequence of PDGF-BB mediated protection from apoptosis (lower caspase-3 activity particularly in cardiomyocytes in PDGF-BB treated vs. untreated EHTs). We confirmed the anti-apoptotic effect of PDGF-BB in monolayer cultures and observed that PI3-kinase inhibition with LY294002 attenuated PDGF-BB-mediated cardiomyocyte protection. We conclude that PDGF-BB does not induce hypertrophy or proliferation, but confers an anti-apoptotic effect on cardiomyocytes. Our findings suggest a further exploitation of PDGF-BB in cardiomyocyte protection in vivo and in vitro.

Keywords: PDGF, Apoptosis, Hypertrophy, Contractility, Tissue engineering