Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts

Yodo Tamaki; Yoshitaka Iwanaga; Shinichiro Niizuma; Tsuneaki Kawashima; Takao Kato; Yasutaka Inuzuka; Takahiro Horie; Hanako Morooka; Toru Takase; Yasumitsu Akahashi; Kazuhiro Kobuke; Koh Ono; Tetsuo Shioi; Søren P Sheikh; Noona Ambartsumian; Eugene Lukanidin; Taka-Aki Koshimizu; Shunichi Miyazaki; Takeshi Kimura

doi:10.1016/j.yjmcc.2013.01.007

Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts

Yodo Tamaki, Yoshitaka Iwanaga, Shinichiro Niizuma, Tsuneaki Kawashima, Takao Kato, Yasutaka Inuzuka, Takahiro Horie, Hanako Morooka, Toru Takase, Yasumitsu Akahashi, Kazuhiro Kobuke, Koh Ono, Tetsuo Shioi, Søren P Sheikh, Noona Ambartsumian, Eugene Lukanidin, Taka-Aki Koshimizu, Shunichi Miyazaki, Takeshi Kimura

37 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Molecular and Cellular Cardiology
Volume	57
Pages (from-to)	72-81
Number of pages	10
ISSN	0022-2828
DOIs	https://doi.org/10.1016/j.yjmcc.2013.01.007
Publication status	Published - Apr 2013

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Tamaki, Y., Iwanaga, Y., Niizuma, S., Kawashima, T., Kato, T., Inuzuka, Y., Horie, T., Morooka, H., Takase, T., Akahashi, Y., Kobuke, K., Ono, K., Shioi, T., Sheikh, S. P., Ambartsumian, N., Lukanidin, E., Koshimizu, T-A., Miyazaki, S., & Kimura, T. (2013). Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts. Journal of Molecular and Cellular Cardiology, 57, 72-81. https://doi.org/10.1016/j.yjmcc.2013.01.007

Tamaki, Y, Iwanaga, Y, Niizuma, S, Kawashima, T, Kato, T, Inuzuka, Y, Horie, T, Morooka, H, Takase, T, Akahashi, Y, Kobuke, K, Ono, K, Shioi, T, Sheikh, SP, Ambartsumian, N, Lukanidin, E, Koshimizu, T-A, Miyazaki, S & Kimura, T 2013, 'Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts', Journal of Molecular and Cellular Cardiology, vol. 57, pp. 72-81. https://doi.org/10.1016/j.yjmcc.2013.01.007

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title = "Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts",

abstract = "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.",

author = "Yodo Tamaki and Yoshitaka Iwanaga and Shinichiro Niizuma and Tsuneaki Kawashima and Takao Kato and Yasutaka Inuzuka and Takahiro Horie and Hanako Morooka and Toru Takase and Yasumitsu Akahashi and Kazuhiro Kobuke and Koh Ono and Tetsuo Shioi and Sheikh, {S{\o}ren P} and Noona Ambartsumian and Eugene Lukanidin and Taka-Aki Koshimizu and Shunichi Miyazaki and Takeshi Kimura",

year = "2013",

month = apr,

doi = "10.1016/j.yjmcc.2013.01.007",

language = "English",

volume = "57",

pages = "72--81",

journal = "Journal of Molecular and Cellular Cardiology",

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TY - JOUR

T1 - Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts

AU - Tamaki, Yodo

AU - Iwanaga, Yoshitaka

AU - Niizuma, Shinichiro

AU - Kawashima, Tsuneaki

AU - Kato, Takao

AU - Inuzuka, Yasutaka

AU - Horie, Takahiro

AU - Morooka, Hanako

AU - Takase, Toru

AU - Akahashi, Yasumitsu

AU - Kobuke, Kazuhiro

AU - Ono, Koh

AU - Shioi, Tetsuo

AU - Sheikh, Søren P

AU - Ambartsumian, Noona

AU - Lukanidin, Eugene

AU - Koshimizu, Taka-Aki

AU - Miyazaki, Shunichi

AU - Kimura, Takeshi

PY - 2013/4

Y1 - 2013/4

N2 - 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.

AB - 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.

U2 - 10.1016/j.yjmcc.2013.01.007

DO - 10.1016/j.yjmcc.2013.01.007

M3 - Journal article

C2 - 23352991

SN - 0022-2828

VL - 57

SP - 72

EP - 81

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

ER -

Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts

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