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Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles.

Publication ,  Journal Article
Wang, X; Tang, H; Wei, EQ; Wang, Z; Yang, J; Yang, R; Wang, S; Zhang, Y; Pitt, GS; Zhang, H; Wang, C
Published in: J Mol Cell Cardiol
March 2017

The intracellular fibroblast growth factors (iFGF/FHFs) bind directly to cardiac voltage gated Na+ channels, and modulate their function. Mutations that affect iFGF/FHF-Na+ channel interaction are associated with arrhythmia syndromes. Although suspected to modulate other ionic currents, such as Ca2+ channels based on acute knockdown experiments in isolated cardiomyocytes, the in vivo consequences of iFGF/FHF gene ablation on cardiac electrical activity are still unknown. We generated inducible, cardiomyocyte-restricted Fgf13 knockout mice to determine the resultant effects of Fgf13 gene ablation. Patch clamp recordings from ventricular myocytes isolated from Fgf13 knockout mice showed a ~25% reduction in peak Na+ channel current density and a hyperpolarizing shift in steady-state inactivation. Electrocardiograms on Fgf13 knockout mice showed a prolonged QRS duration. The Na+ channel blocker flecainide further prolonged QRS duration and triggered ventricular tachyarrhythmias only in Fgf13 knockout mice, suggesting that arrhythmia vulnerability resulted, at least in part, from a loss of functioning Na+ channels. Consistent with these effects on Na+ channels, action potentials in Fgf13 knockout mice, compared to Cre control mice, exhibited slower upstrokes and reduced amplitude, but unexpectedly had longer durations. We investigated candidate sources of the prolonged action potential durations in myocytes from Fgf13 knockout mice and found a reduction of the transient outward K+ current (Ito). Fgf13 knockout did not alter whole-cell protein levels of Kv4.2 and Kv4.3, the Ito pore-forming subunits, but did decrease Kv4.2 and Kv4.3 at the sarcolemma. No changes were seen in the sustained outward K+ current or voltage-gated Ca2+ current, other candidate contributors to the increased action potential duration. These results implicate that FGF13 is a critical cardiac Na+ channel modulator and Fgf13 knockout mice have increased arrhythmia susceptibility in the setting of Na+ channel blockade. The unanticipated effect on Ito revealed new FGF13 properties and the unexpected lack of an effect on voltage-gated Ca2+ channels highlight potential compensatory changes in vivo not readily revealed with acute Fgf13 knockdown in cultured cardiomyocytes.

Duke Scholars

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

March 2017

Volume

104

Start / End Page

63 / 74

Location

England

Related Subject Headings

  • Tachycardia, Ventricular
  • Sodium Channels
  • Myocytes, Cardiac
  • Mice, Knockout
  • Mice
  • Male
  • Ion Channels
  • Genetic Predisposition to Disease
  • Genetic Loci
  • Gene Targeting
 

Citation

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Wang, X., Tang, H., Wei, E. Q., Wang, Z., Yang, J., Yang, R., … Wang, C. (2017). Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles. J Mol Cell Cardiol, 104, 63–74. https://doi.org/10.1016/j.yjmcc.2017.01.009
Wang, Xiangchong, He Tang, Eric Q. Wei, Zhihua Wang, Jing Yang, Rong Yang, Sheng Wang, et al. “Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles.J Mol Cell Cardiol 104 (March 2017): 63–74. https://doi.org/10.1016/j.yjmcc.2017.01.009.
Wang X, Tang H, Wei EQ, Wang Z, Yang J, Yang R, et al. Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles. J Mol Cell Cardiol. 2017 Mar;104:63–74.
Wang, Xiangchong, et al. “Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles.J Mol Cell Cardiol, vol. 104, Mar. 2017, pp. 63–74. Pubmed, doi:10.1016/j.yjmcc.2017.01.009.
Wang X, Tang H, Wei EQ, Wang Z, Yang J, Yang R, Wang S, Zhang Y, Pitt GS, Zhang H, Wang C. Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles. J Mol Cell Cardiol. 2017 Mar;104:63–74.
Journal cover image

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

March 2017

Volume

104

Start / End Page

63 / 74

Location

England

Related Subject Headings

  • Tachycardia, Ventricular
  • Sodium Channels
  • Myocytes, Cardiac
  • Mice, Knockout
  • Mice
  • Male
  • Ion Channels
  • Genetic Predisposition to Disease
  • Genetic Loci
  • Gene Targeting