Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Tinsley Harrison Tower 611L, 1720 2nd Avenue South, Birmingham, AL, 35294, USA.
Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
Sci Rep. 2022 May 5;12(1):7326. doi: 10.1038/s41598-022-11033-x.
Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.
成纤维细胞生长因子 21（FGF21）是一种增加胰岛素敏感性的激素，已被证明是一种有希望的治疗药物，可改善代谢失调。在这里，我们报告 FGF21 通过结合β-klotho 和成纤维细胞生长因子受体（FGFR）4 直接靶向心肌细胞。在高葡萄糖的作用下，FGF21 通过细胞外信号调节激酶 1/2（ERK1/2）信号诱导心肌细胞宽度的生长。虽然短期升高 FGF21 可以起到心脏保护作用，但我们发现，在 2 型糖尿病（T2D）小鼠中，血清 FGF21 水平升高，FGFR4 激活诱导心脏向心性肥大。由于 T2D 患者存在射血分数保留的心力衰竭（HFpEF）的风险，我们提出，升高的 FGF21-FGFR4 信号诱导向心性肥大可能构成促进 T2D 相关 HFpEF 的新机制，因此 FGFR4 阻断可能成为 T2D 的心脏保护治疗方法。此外，目前正在临床试验中的 FGF21 类似物的潜在不良心脏效应应进行研究。
