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Cardiovascular Research Advance Access first published online on November 2, 2009
This version [Corrected Proof] published online on November 26, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp360
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

TWEAK is a positive regulator of cardiomyocyte proliferation

Tatyana Novoyatleva1, Florian Diehl1, Machteld J. van Amerongen1, Chinmoy Patra1, Fulvia Ferrazzi2, Riccardo Bellazzi2 and Felix B. Engel1,*

1 Department of Cardiac Development and Remodelling, Excellence Cluster Cardio-Pulmonary System, Max Planck Institute for Heart and Lung Research, Parkstrasse 1, Bad Nauheim 61231, Germany
2 Dipartimento di Informatica e Sistemistica, Università degli Studi di Pavia, via Ferrata 1, Pavia 27100, Italy

* Corresponding author. Tel: +49 6032 705 248, Fax: +49 6032 705 211, Email: felix.engel{at}mpi-bn.mpg.de

Aims: Proliferation of mammalian cardiomyocytes stops during the first weeks after birth, preventing the heart from regenerating after injury. Recently, several studies have indicated that induction of cardiomyocyte proliferation can be utilized to regenerate the mammalian heart. Thus, it is important to identify novel factors that can induce proliferation of cardiomyocytes. Here, we determine the effect of TNF-related weak inducer of apoptosis (TWEAK) on cardiomyocytes, a cytokine known to regulate proliferation in several other cell types.

Methods and results: Stimulation of neonatal rat cardiomyocytes with TWEAK resulted in increased DNA synthesis, increased expression of the proliferative markers Cyclin D2 and Ki67, and downregulation of the cell cycle inhibitor p27KIP1. Importantly, TWEAK stimulation resulted also in mitosis (H3P), cytokinesis (Aurora B), and increased cardiomyocyte numbers. Loss of function experiments revealed that re-induction of proliferation was dependent on tumour necrosis factor receptor superfamily member 12A (FN14) signalling. Downstream signalling was mediated through activation of extracellular signal-regulated kinases and phosphatidylinositol 3-kinase as well as inhibition of glycogen synthase kinase-3beta. In contrast to neonatal cardiomyocytes, TWEAK had no effect on adult rat cardiomyocytes due to developmental downregulation of its receptor FN14. However, adenoviral expression of FN14 enabled efficient induction of cell cycle re-entry in adult cardiomyocytes after TWEAK stimulation.

Conclusion: Our data establish TWEAK as a positive regulator of cardiomyocyte proliferation.

KEYWORDS TWEAK; FN14; Heart; Cardiomyocytes; Proliferation; Signalling

Time for primary review: 35 days


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