Cardiac Fgf21 synthesis and release: an autocrine loop for boosting up antioxidant defenses in failing hearts.

Abstract

Fibroblast growth factors (Fgfs) are signalling proteins of ∼150–300 amino acids with diverse functions, mainly in development and metabolism. The human/mouse Fgf family comprises 22 members. Fgfs can be classified as intracellular, paracrine, and endocrine Fgfs by their action mechanisms. Among Fgfs, Fgf2, Fgf16, Fgf21, and Fgf23 have been shown to be cardiomyokines playing pathophysiological roles in the heart.1 Fgf2 and Fgf16 are paracrine Fgfs, which usually function in an autocrine/paracrine manner. In contrast, so far Fgf21 and Fgf23 have been reported to function in an endocrine manner. Cardiac Fgf2 promotes cardiac hypertrophy and fibrosis by activating MAPK signalling through the activation of Fgf receptor (Fgfr). In contrast, cardiac Fgf16 may prevent them by competing with Fgf2 for the binding site of Fgfr. Although Fgf23 is an endocrine Fgf, cardiac Fgf23 induces cardiac hypertrophy by activating calcineurin/NFAT signalling in an autocrine/paracrine manner.1 Fgf21 is usually known to be a hepatic hormone involved in the control of glucose, lipid, and energy metabolism. These actions of Fgf21 are mediated by activating MAPK signalling through the activation of Fgfr in an endocrine manner.2 Fgf21 is also produced in the heart and prevents cardiac hypertrophy by activating MAPK signalling through the activation of Fgfr.3 Cardiac Fgf21 expression is induced by the protein deacetylase Sirt1,3 which protects against hypertrophy, ischaemia–reperfusion injury, and oxidative stress in the …