Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts.
Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53-downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yodo
Y
Tamaki
Yoshitaka
Y
Iwanaga
Shinichiro
S
Niizuma
Tsuneaki
T
Kawashima
Takao
T
Kato
Yasutaka
Y
Inuzuka
Takahiro
T
Horie
Hanako
H
Morooka
Toru
T
Takase
Yasumitsu
Y
Akahashi
Kazuhiro
K
Kobuke
Koh
K
Ono
Tetsuo
T
Shioi
Søren P
SP
Sheikh
Noona
N
Ambartsumian
Eugene
E
Lukanidin
Taka-Aki
TA
Koshimizu
Shunichi
S
Miyazaki
Takeshi
T
Kimura
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism* / Q000502:physiology; D041681:NIH 3T3 Cells; D020097:Natriuretic Peptide, Brain / Q000097:blood; D051381:Rats; D020303:Rats, Inbred Dahl; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000502:physiology*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C526316:CCN2 protein, rat; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C499412:S100a4 protein, rat; D016159:Tumor Suppressor Protein p53; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor; D003094:Collagen