S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes.
OBJECTIVE
The multifunctional Ca2+-binding protein S100A4 (also known as Mts1 and Fsp1) is involved in fibrosis and tissue remodeling in several diseases including cancer, kidney fibrosis, central nervous system injury, and pulmonary vascular disease. We previously reported that S100A4 mRNA expression was increased in hypertrophic rat hearts and that it has pro-cardiomyogenic effects in embryonic stem cell-derived embryoid bodies. We therefore hypothesized that S100A4 could play a supportive role in the injured heart.


RESULTS
Here we verify by quantitative real-time PCR and immunoblotting that S100A4 mRNA and protein is upregulated in hypertrophic rat and human hearts and show by way of confocal microscopy that S100A4 protein, but not mRNA, appears in cardiac myocytes only in the border zone after an acute ischemic event in rat and human hearts. In normal rat and human hearts, S100A4 expression primarily colocalizes with markers of fibroblasts. In hypertrophy elicited by aortic banding/stenosis or myocardial infarction, this expression is increased. Moreover, invading macrophages and leucocytes stain strongly for S100A4, further increasing cardiac levels of S100A4 protein after injury. Promisingly, recombinant S100A4 protein elicited a robust hypertrophic response and increased the number of viable cells in cardiac myocyte cultures by inhibiting apoptosis. We also found that ERK1/2 activation was necessary for both the hypertrophy and survival effects of S100A4 in vitro.


CONCLUSIONS
Along with proposed angiogenic and cell motility stimulating effects of S100A4, these findings suggest that S100A4 can act as a novel cardiac growth and survival factor and may have regenerative effects in injured myocardium.
Schneider
Mikael
M
The Laboratory of Molecular and Cellular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Medicine B, H:S Rigshospitalet, Copenhagen University Hospital, Denmark.
Kostin
Sawa
S
Strøm
Claes C
CC
Aplin
Mark
M
Lyngbaek
Stig
S
Theilade
Juliane
J
Grigorian
Mariam
M
Andersen
Claus B
CB
Lukanidin
Eugene
E
Lerche Hansen
Jakob
J
Sheikh
Søren P
SP
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation; D014746:Vimentin / Q000032:analysis / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D048049:Extracellular Signal-Regulated MAP Kinases; D018809:Proliferating Cell Nuclear Antigen; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014746:Vimentin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C499412:S100a4 protein, rat