FGF21-FGFR4 signaling in cardiac remodeling
Endocrinology, Diabetology, Metabolism
Final Report Abstract
LVH is an important mechanism of cardiovascular disease and diabetic patients are more than twice as likely to die from heart failure. To date the precise molecular mechanisms underlying this pathological interrelationship remain largely unknown. Fibroblast growth factor (FGF) 21 is an adipokine that is mainly produced by hepatocytes. FGF21 effects are mediated by FGF receptors (FGFR) that in mammals exist in four isoforms (FGFR1-4). In complex with its co-receptor β-klotho, FGF21 binds FGFR1, 2 and 3, but not FGFR4, and thereby induces Ras/mitogen-activated protein kinase (MAPK) signaling and downstream effects in adipocytes. It is closely related to FGF23, a bone-derived, phosphate-regulating hormone, that can directly target cardiac myocytes and induce cardiac hypertrophy in vitro and in vivo, thereby contributing to pathologic cardiac remodeling that is known to be associated with chronic kidney disease (CKD). Similar to FGF23 in CKD, FGF21 serum levels are elevated in animal models and in patients with type 2 diabetes, but since the heart does not express β-klotho, it has been assumed that FGF21 cannot directly affect cardiac morphology and function and induce cardiac injury. In this study we show that FGF21 can directly target cardiac myocytes through activation of FGFR4 followed by subsequent initiation of PLCγ/calcineurin/NFAT signaling and the induction of hypertrophic growth in a β-klotho independent manner. This is in sharp contrast to “classic” FGF21 target cells, such as adipocytes, that express β-klotho and respond to FGF21 with an activation of the Ras/MAPK signaling cascade. Therefore we conclude that depending on the FGFR isoform and the presence or absence of β-klotho, FGF21 can activate distinct downstream signaling pathways, and supports our hypothesis that by stimulating PLCγ/calcineurin/NFAT signaling in cardiac myocytes, FGF21 has direct pathologic effects on the heart.
