FGF23 promotes myocardial fibrosis in mice through activation of β-catenin

// Huixin Hao 1,* , Xixian Li 1,* , Qingman Li 1,* , Hairuo Lin 1 , Zhenhuan Chen 1 , Jiahe Xie 1 , Wanling Xuan 1 , Wangjun Liao 2 , Jianping Bin 1 , Xiaobo Huang 1 , Masafumi Kitakaze 1,3 and Yulin Liao 1 1 State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China 3 Cardiovascular Division of the Department of Medicine, National Cerebral and Cardiovascular Center, Fujishirodai, Suita, Osaka, Japan * These authors have contributed equal to this study Correspondence to: Yulin Liao, email: // Keywords : fibroblast growth factor 23, β-catenin, TGF-β, myocardial fibrosis, ischemia/reperfusion, Pathology Section Received : August 15, 2016 Accepted : August 21, 2016 Published : August 25, 2016 Abstract Fibroblast growth factor 23 (FGF23) has been reported to induce left ventricular hypertrophy, but it remains unclear whether FGF23 plays a role in cardiac fibrosis. This study is attempted to investigate the role of FGF23 in post-infarct myocardial fibrosis in mice. We noted that myocardial and plasma FGF23 and FGF receptor 4 were increased in mice with heart failure as well as in cultured adult mouse cardiac fibroblasts (AMCFs) exposed to angiotensin II, phenylephrine, soluble fractalkine. Recombinant FGF23 protein increased active β-catenin , procollagen I and procollagen III expression in cultured AMCFs. Furthermore, intra-myocardial injection of adeno-associated virus-FGF23 in mice significantly increased left ventricular end-diastolic pressure and myocardial fibrosis, and markedly upregulated active β-catenin, transforming growth factor β (TGF-β), procollagen I and procollagen III in both myocardial infarction (MI) and ischemia/reperfusion (IR) mice, while β-catenin inhibitor or silencing of β-catenin antagonized the FGF23-promoted myocardial fibrosis in vitro and in vivo. These findings indicate that FGF23 promotes myocardial fibrosis and exacerbates diastolic dysfunction induced by MI or IR, which is associated with the upregulation of active β-catenin and TGF-β.