S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes

TY - JOUR

T1 - S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes

AU - Schneider, Mikael

AU - Kostin, Sawa

AU - Strøm, Claes C

AU - Aplin, Mark

AU - Lyngbaek, Stig

AU - Theilade, Juliane

AU - Grigorian, Mariam

AU - Andersen, Claus B

AU - Lukanidin, Eugene

AU - Lerche Hansen, Jakob

AU - Sheikh, Søren P

N1 - Keywords: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biological Markers; Blotting, Western; Cardiomegaly; Cell Survival; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Humans; Immunohistochemistry; Microscopy, Confocal; Myocytes, Cardiac; Phosphorylation; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; S100 Proteins; Up-Regulation; Vimentin

PY - 2007

Y1 - 2007

N2 - 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. METHODS AND 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.

AB - 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. METHODS AND 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.

U2 - 10.1016/j.cardiores.2007.03.027

DO - 10.1016/j.cardiores.2007.03.027

M3 - Journal article

C2 - 17466960

SN - 0008-6363

VL - 75

SP - 40

EP - 50

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 1

ER -