Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current
Summary
Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of NaV1.5 inactivation results in a small persistent Na influx known as late Na current (I Na,L), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. Here, using low-noise multi-channel recordings in heterologous systems, LQTS3 patient-derived iPSCs cardiomyocytes, and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1-4) tune pathogenic I Na,L in an isoform-specific manner. This scheme suggests a complex orchestration of I Na,L in cardiomyocytes that may contribute to variable disease expressivity of NaV1.5 channelopathies. We further leverage these observations to engineer a peptide-inhibitor of I Na,L with a higher efficacy as compared to a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I Na,L in pathophysiology and outline potential therapeutic avenues.
| Authors | Chakouri N, Rivas S, Roybal D, Yang L, Diaz J, Hsu A, Mahling R, Chen BX, Owoyemi JO, DiSilvestre D, Sirabella D, Corneo B, Tomaselli GF, Dick IE, Marx SO, Ben-Johny M |
|---|---|
| Journal | Nature cardiovascular research |
| Publication Date | 2022 May;1(5):1-13 |
| PubMed | 35662881 |
| PubMed Central | PMC9161660 |
| DOI | 10.1038/s44161-022-00060-6 |