Angiotensin II‐induced cardiac hypertrophy and fibrosis are promoted in mice lacking Fgf16

Abstract

Fibroblast growth factors (Fgfs) are pleiotropic proteins involved in development, repair and metabolism. Fgf16 is predominantly expressed in the heart. However, as the heart function is essentially normal in Fgf16 knockout mice, its role has remained unclear. To elucidate the pathophysiological role of Fgf16 in the heart, we examined angiotensin II-induced cardiac hypertrophy and fibrosis in Fgf16 knockout mice. Angiotensin II-induced cardiac hypertrophy and fibrosis were significantly promoted by enhancing Tgf-β1 expression in Fgf16 knockout mice. Unexpectedly, the response to cardiac remodeling was apparently opposite to that in Fgf2 knockout mice. These results indicate that Fgf16 probably prevents cardiac remodeling, although Fgf2 promotes it. Cardiac Fgf16 expression was induced after the induction of Fgf2 expression by angiotensin II. In cultured cardiomyocytes, Fgf16 expression was promoted by Fgf2. In addition, Fgf16 antagonized Fgf2-induced Tgf-β1 expression in cultured cardiomyocytes and noncardiomyocytes. These results suggest a possible mechanism whereby Fgf16 prevents angiotensin II-induced cardiac hypertrophy and fibrosis by antagonizing Fgf2. The present findings should provide new insights into the roles of Fgf signaling in cardiac remodeling.

Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction

“…Previous studies using FGF2-deficient and -overexpressing mutant mice have shown that FGF2 is a critical mediator of cardiac hypertrophy in response to transaortic constriction (TAC) or renal-induced hypertension (37)(38)(39). Similar to the expression of CTGF, FGF2 is mainly synthesized by CFs in response to myocardial stress (40,41). We found that the expression of FGF2 and other hypertrophic markers, as well as the activation of ERK and p38 MAPK, were increased in heart tissues after Ang II infusion.…”

GATA4 regulates Fgf16 to promote heart repair after injury

“…Importantly, previous reports showed that FGF2 is expressed in non-cardiomyocytes and has a positive effect on cardiomyocyte replication, angiogenesis, collagen synthesis, and infarct repair or hypertrophy (Kaye et al, 1996;Virag et al, 2007;House et al, 2010). It has been reported that FGF16 blocks FGF2 function by competing with FGF2 for binding to its receptor FGFR1c (FGF receptor 1c) (Lu et al, 2008), and in doing so might, therefore, inhibit cardiac hypertrophy and fibrosis (Matsumoto et al, 2013;Santiago et al, 2014). Altogether, previous findings indicate that FGF16 in the extracellular matrix might promote the inhibition of fibrosis and hypertrophy, or provide a niche for cardiac progenitors to drive regeneration.…”

Heart-specific expression of FGF-16 and a potential role in postnatal cardioprotection

“…FGF-16 can bind to FGFR1, but also other FGFRs with high affinity [14,56]. FGF-16 does not appear, however, to have a strong effect on postnatal cardiac myocyte proliferation, based on exogenous treatment of neonatal rat cardiac myocyte cultures and the cardiac phenotype of FGF-16 null C57BL/6 mice [14,57]. The fact that FGF-16 can bind multiple FGFRs raises the possibility of both shared but also antagonistic function with other FGF family member and affecting signaling.…”