Abstract 13917: Metastasis-associated Protein S100A4 Contributes to Cardiac Fibrosis through the Modulation of PTEN
Background: The calcium-binding protein S100A4 possesses a wide range of biological functions and promotes metastasis. Recently, in non-cancer diseases such as kidney diseases, liver fibrosis and rheumatoid arthritis, S100A4 is reported to be upregulated and involved in the process of epithelial-mesenchymal transition and fibrosis. However, the role of S100A4 in the myocardium is unclear. Therefore, we investigated the role of S100A4 in cardiac hypertrophy and heart failure (HF) using experimental rodent models.
Methods and Results: In Dahl rat hypertensive HF model, cardiac S100A4 was upregulated in the compensatory hypertrophic phase (2.8-fold increase in protein level) and further upregulated during the transition to HF (4.5-fold increase). It was mainly expressed in interstitial cells such as fibroblasts, macrophages and leucocytes. To investigate the precise role of S100A4 in the myocardium, transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline phenotype as wild type (WT) mice. Although S100A4 mRNA was 3.7-fold increased in left ventricle (LV) of WT mice at one week after TAC, there was no difference between WT mice and KO mice in hypertrophic response. However, KO mice showed reduced interstitial fibrosis (fibrotic area, 2.7% in KO vs. 7.4% in WT; p<0.05) and the decreased number of myofibroblasts in LV. The expression of collagens and profibrotic cytokines such as TGF-β1 and connective tissue growth factor was significantly suppressed in KO mice compared with WT mice. It was associated with the increased expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10) in KO mice, which is recently reported to be a negative regulator of myofibroblast differentiation in pulmonary fibrosis. In addition, the knockdown of S100A4 by short hairpin RNA in in vitro cardiac fibroblasts significantly increased PTEN expression and decreased collagen expression.
Conclusions: These findings suggest that cardiac S100A4 mediates interstitial cardiac fibrosis, probably through the modulation of PTEN in cardiac fibroblasts. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.
- © 2010 by American Heart Association, Inc.