Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles.
Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles.
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小鼠心脏中 Fgf13 的条件性敲除会增加心律失常的易感性并揭示新的离子通道调节作用
DOI：
10.1016/j.yjmcc.2017.01.009
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发表时间：
2017-03
影响因子：
5
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Wang X;Tang H;Wei EQ;Wang Z;Yang J;Yang R;Wang S;Zhang Y;Pitt GS;Zhang H;Wang C
细胞内成纤维细胞生长因子（iFGF/FHF）直接与心脏电压门控Na+通道结合，并调节其功能。影响iFGF/FHF-Na+通道相互作用的突变与心律失常综合征相关。尽管基于在分离的心肌细胞中的急性敲除实验，怀疑iFGF/FHF基因消融可调节其他离子电流，例如Ca 2+通道，但iFGF/FHF基因消融对心脏电活动的体内后果仍然未知。我们产生了可诱导的，心肌细胞限制性Fgf 13基因敲除小鼠，以确定Fgf 13基因消融的结果。从Fgf 13基因敲除小鼠分离的心室肌细胞的膜片钳记录显示峰值Na+通道电流密度降低约25%，稳态失活发生超极化转变。Fgf 13基因敲除小鼠的心电图显示QRS持续时间延长。Na+通道阻滞剂氟卡尼进一步延长QRS持续时间，仅在Fgf 13基因敲除小鼠中触发室性快速性心律失常，这表明心律失常脆弱性至少部分是由于功能性Na+通道的丧失。与对Na+通道的这些作用一致，与Cre对照小鼠相比，Fgf 13敲除小鼠的动作电位表现出较慢的上升和降低的幅度，但出乎意料地具有较长的持续时间。我们研究了FGF 13基因敲除小鼠肌细胞动作电位持续时间延长的候选来源，发现瞬时外向K+电流（Ito）减少。Fgf 13基因敲除并没有改变Ito孔形成亚基Kv4.2和Kv4.3的全细胞蛋白水平，但却降低了肌膜上的Kv4.2和Kv4.3。在持续外向K+电流或电压门控性Ca 2+电流中未观察到变化，这是增加动作电位持续时间的其他候选因素。这些结果表明，FGF 13是一个关键的心脏Na+通道调节剂和Fgf 13基因敲除小鼠具有增加的心律失常易感性的设置中的Na+通道阻滞。对Ito的意外影响揭示了新的FGF 13特性，并且意外地缺乏对电压门控Ca 2+通道的影响，突出了在培养的心肌细胞中急性FGF 13敲低不容易揭示的体内潜在代偿性变化。
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.
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影响因子：
3.7
作者：
Hsu WC;Nenov MN;Shavkunov A;Panova N;Zhan M;Laezza F
通讯作者：
Laezza F
影响因子：
5.3
作者：
Laezza, Fernanda;Gerber, Benjamin R.;Nerbonne, Jeanne M.
通讯作者：
Nerbonne, Jeanne M.
影响因子：
5.3
作者：
Puranam, Ram S.;He, Xiao Ping;McNamara, James O.
通讯作者：
McNamara, James O.
DOI：
10.1073/pnas.93.18.9850
发表时间：
1996-09-03
影响因子：
11.1
作者：
Smallwood, PM;MunozSanjuan, I;Nathans, J
通讯作者：
Nathans, J
影响因子：
20.1
作者：
Sohal, DS;Nghiem, M;Molkentin, JD
通讯作者：
Molkentin, JD