| dc.description.abstract |
<p>Fibroblast growth factor homologous factors (FHFs) are non-canonical members of
the fibroblast growth factor family (FGF11-14) that were initially discovered to bind
and regulate neuronal and cardiac voltage-gated Na+ channels. Loss-of-function mutations
that disrupt interaction between FHFs and Na+ channels cause spinocerebellar ataxias
and cardiac arrhythmias such as Brugada syndrome. Although recent studies in brain
of FHF knockout mice suggested novel functions for FHFs beyond ion channel modulation,
it is unclear whether FHFs in the heart serve additional roles beyond regulating cardiac
excitability. In this study, we performed a proteomic screen to identify novel interacting
proteins for FGF13 in mouse heart. Mass spectrometry analysis revealed an interaction
between FGF13 and a complex of cavin proteins that regulate caveolae, membrane invaginations
that organize protective signaling pathways and provide a reservoir to buffer membrane
stress. FGF13 controls the relative distribution of cavin 1 between the plasma membrane
and cytosol and thereby acts as a negative regulator of caveolae. In inducible, cardiac-specific
Fgf13 knockout mice, cavin 1 redistributed to the plasma membrane and stabilized the
caveolar structural protein caveolin 3, leading to an increased density of caveolae.
In a transverse aortic constriction model of pressure overload, this increased caveolar
abundance enhanced cardioprotective signaling through the caveolar-organized PI3 kinase
pathway, preserving cardiac function and reducing fibrosis. Additionally, the increased
caveolar reserve provided mechanoprotection, as indicated by reduced membrane rupture
in response to hypo-osmotic stress. Thus, our results establish FGF13 as a novel regulator
of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling, and suggest
that inhibition of FHFs in the adult heart may have cardioprotective benefits in the
setting of maladaptive hypertrophy.</p>
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