FGF12A Regulates Nav1.5 via CaM-regulated and CaM-independent Mechanisms

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract Opening of the cardiac voltage-gated Na+ channel (Nav1.5) is responsible for robust depolarization action potential, while inactivation, which rapidly follows, allows repolarization. Regulation both voltage- and time-dependent kinetics Nav1.5 inactivation can alter ability heart to initiate sustain a re-entrant arrhythmia. The C-terminal domain (CTD) has been shown modulate fast channel, multiple auxiliary proteins bind CTD, including calmodulin (CaM) intracellular fibroblast growth factor 12A (FGF12A). Recently, non-canonical CaM-binding site was also discovered on N-terminal A-splice variants iFGFs. We performed cut-open Vaseline gap (COVG) voltage-clamp test whether FGF12A with without CaM regulates gating. In WT channels, present had minimal effect voltage dependence activation inactivation. Conversely, when absent CTD (IQ/AA), dramatic shift in steady-state (SSI) occurred, regardless FGF12A. These two distinct mechanisms are operative LQT3 mutations where requires voltage-dependence but not inhibit persistent late current. conclude that there by modulates channel: CaM-regulated alteration CaM-independent inhibition

Language: Английский

Loss of macrophage fibroblast growth factor 12 attenuates cardiac fibrosis in pressure-overloaded myocardium

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 154, P. 114614 - 114614

Published: April 7, 2025

Language: Английский

The FGF13‐Caveolin‐1 Axis: A Key Player in the Pathogenesis of Doxorubicin‐ and D‐Galactose‐Induced Premature Cardiac Aging

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Abstract Delaying senescence of cardiomyocytes has garnered widespread attention as a potential target for preventing cardiovascular diseases (CVDs). FGF13 (Fibroblast growth factor 13) been implicated in various pathophysiological processes. However, its role premature myocardial aging and cardiomyocyte remains unknown. Adeno‐associated virus 9 (AAV9) vectors expressing cardiac‐specific Fgf13 knockout (Fgf13KO) mice are utilized to reveal that overexpression deficiency exacerbated alleviated Doxorubicin/D‐galactose‐induced characteristics functional impairment, respectively. Transcriptomics employed identify an association between Caveolin‐1 (Cav1). Mechanistic studies indicated regulated the Cav1 promoter activity expression through p38/MAPK pathway nuclear translocation p65, well binding level PTRF mediate senescence. Furthermore, murine hearts reversed alleviatory effects on phenotype dysfunction. This study demonstrated Cav1‐p53‐p21 axis augment thereby cardiac suggests knockdown may be promising approach combat CVDs response chemotoxicity.

Language: Английский