Fibrosis growth factor 23 is a promoting factor for cardiac fibrosis in the presence of transforming growth factor-β1

被引:34
|
作者
Kuga, Kazuhiro [1 ]
Kusakari, Yoichiro [1 ]
Uesugi, Ken [1 ,2 ]
Semba, Kentaro [2 ]
Urashima, Takashi [3 ]
Akaike, Toru [1 ]
Minamisawa, Susumu [1 ,2 ]
机构
[1] Jikei Univ, Sch Med, Dept Cell Physiol, Tokyo, Japan
[2] Waseda Univ, Dept Life Sci & Med Biosci, Tokyo, Japan
[3] Jikei Univ, Sch Med, Dept Pediat, Tokyo, Japan
来源
PLOS ONE | 2020年 / 15卷 / 04期
关键词
FGF23; RECEPTOR; HEART; ACTIVATION; PRESSURE;
D O I
10.1371/journal.pone.0231905
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Myocardial fibrosis is often associated with cardiac hypertrophy; indeed, fibrosis is one of the most critical factors affecting prognosis. We aimed to identify the molecules involved in promoting fibrosis under hypertrophic stimuli. We previously established a rat model of cardiac hypertrophy by pulmonary artery banding, in which approximately half of the animals developed fibrosis in the right ventricle. Here, we first comprehensively analyzed mRNA expression in the right ventricle with or without fibrosis in pulmonary artery banding model rats by DNA microarray analysis (GSE141650 at NCBI GEO). The expression levels of 19 genes were up-regulated more than 1.5-fold in fibrotic hearts compared with non-fibrotic hearts. Among them, fibrosis growth factor (FGF) 23 showed one of the biggest increases in expression. Real-time PCR analysis also revealed that, among the FGF receptor (FGFR) family, FGFR1 was highly expressed in fibrotic hearts. We then found that FGF23 was expressed predominantly in cardiomyocytes, while FGFR1 was predominantly expressed in fibroblasts in the rat ventricle. Next, we added FGF23 and transforming growth factor (TGF)-beta 1 (10-50 ng/mL of each) to isolated fibroblasts from normal adult rat ventricles and cultured them for three days. While FGF23 itself did not directly affect the expression levels of any fibrosis-related mRNAs, FGF23 enhanced the effect of TGF-beta 1 on increasing the expression levels of alpha-smooth muscle actin (alpha-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-beta 1 and FGF23 was attenuated by the inhibition of FGFR1 or the knockdown of FGFR1 in fibroblasts. Thus, FGF23 synergistically promoted the activation of fibroblasts with TGF-beta 1, transforming fibroblasts into myofibroblasts via FGFR1. Thus, we identified FGF23 as a paracrine factor secreted from cardiomyocytes to promote cardiac fibrosis under conditions in which TGF-beta 1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.
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页数:14
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