TWEAK is a positive regulator of cardiomyocyte proliferation.
OBJECTIVE
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.


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.


CONCLUSIONS
Our data establish TWEAK as a positive regulator of cardiomyocyte proliferation.
Novoyatleva
Tatyana
T
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.
Diehl
Florian
F
van Amerongen
Machteld J
MJ
Patra
Chinmoy
C
Ferrazzi
Fulvia
F
Bellazzi
Riccardo
R
Engel
Felix B
FB
D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D056742:Cyclin D2 / Q000378:metabolism; D000074049:Cytokine TWEAK; D005260:Female; D015870:Gene Expression / Q000502:physiology; D019394:Ki-67 Antigen / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D011247:Pregnancy; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D000074049:Cytokine TWEAK; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613300:Tnfrsf12a protein, rat; C497771:Tnfsf12 protein, rat; D048069:Tumor Necrosis Factors