Abstract
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)-β1 (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-β1 on increasing the expression levels of α-smooth muscle actin (α-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-β1 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-β1, 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-β1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.
Highlights
Cardiac fibrosis often follows cardiac hypertrophy induced by pressure overload
We focused on fibrosis growth factor (FGF) 23 because a previous study had reported that FGF23 plays an important role in cardiac hypertrophy [8]
Our study indicates that hypertrophic stimuli may not be sufficient to induce FGF23 in the heart, a number of previous studies have demonstrated that FGF23 is associated with myocardial hypertrophy [8,9,10]
Summary
Cardiac fibrosis often follows cardiac hypertrophy induced by pressure overload. It stiffens the heart to provide resistance to pressure overload, and promotes diastolic dysfunction of the heart. Because cardiac fibrosis is rarely reversible, controlling cardiac fibrosis is important to reduce the risk of heart failure. Studies on the molecular mechanisms of cardiac fibrosis have identified transforming growth factor (TGF)-β1 as one of the most important factors involved in fibrosis. TGF-β1 is known to be related to both hypertrophy and fibrosis [1, 2]. Distinguishing between a factor for myocardial fibrosis and a hypertrophic factor is challenging because myocardial fibrosis and cardiac hypertrophy typically occur together
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