TWEAK is a positive regulator of cardiomyocyte proliferation

Tatyana Novoyatleva, Florian Diehl, MacHteld J. Van Amerongen, Chinmoy Patra, Fulvia Ferrazzi, Riccardo Bellazzi, Felix B. Engel

Research output: Contribution to journalArticle

Abstract

AimsProliferation 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 resultsStimulation 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.ConclusionOur data establish TWEAK as a positive regulator of cardiomyocyte proliferation.

Original languageEnglish
Pages (from-to)681-690
Number of pages10
JournalCardiovascular Research
Volume85
Issue number4
DOIs
Publication statusPublished - Mar 2010

Keywords

  • Cardiomyocytes
  • FN14
  • Heart
  • Proliferation
  • Signalling
  • TWEAK

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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  • Cite this

    Novoyatleva, T., Diehl, F., Van Amerongen, M. J., Patra, C., Ferrazzi, F., Bellazzi, R., & Engel, F. B. (2010). TWEAK is a positive regulator of cardiomyocyte proliferation. Cardiovascular Research, 85(4), 681-690. https://doi.org/10.1093/cvr/cvp360