Fibroblast Growth Factor 21 Ameliorates Na(V)1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes.
Fibroblast Growth Factor 21 Ameliorates Na(V)1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes.
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成纤维细胞生长因子 21 改善人 AC16 心肌细胞中的 Na(V)1.5 和 Kir2.1 通道失调
DOI：
10.3389/fphar.2021.715466
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发表时间：
2021
影响因子：
5.6
通讯作者：
Yang B
中科院分区：
文献类型：
--
作者：
Li J;Li Y;Liu Y;Yu H;Xu N;Huang D;Xue Y;Li S;Chen H;Liu J;Li Q;Zhao Y;Zhang R;Xue H;Sun Y;Li M;Li P;Liu M;Zhang Z;Li X;Du W;Wang N;Yang B
心肌缺血易引起致死性室性心律失常，室性心律失常仍然是心肌缺血患者死亡的主要原因。肝源性成纤维细胞生长因子21（FGF 21）是一种内分泌调节因子，通过促进糖和脂质代谢发挥代谢作用。新出现的证据显示FGF 21对心血管疾病的有益作用，但FGF 21对人类心肌梗死（MI）后室性心律失常的作用从未得到解决。本研究旨在研究FGF 21对人类MI后心肌细胞的药理学作用。急性心肌梗死心律失常患者和健康志愿者入组本研究。在MI发作后第1天和第7-10天从这些受试者收集血清样品，用于使用ELISA测量FGF 21水平。在此，我们发现相对于对照样品，在MI发作后第1天FGF 21的血清水平显著增加，并且在第7-10天恢复正常。为了阐明FGF 21对心律失常的调节作用，本研究建立了两种心律失常动物模型，即缺血性心律失常模型（MI大鼠模型）和非缺血性心律失常模型（哇巴因诱导的豚鼠心律失常模型）。结果显示，rhbFGF 21治疗组大鼠心肌梗死后不同时间点缺血性心律失常的发生率和持续时间均明显低于生理盐水治疗组。此外，在哇巴因模型中，与rhbFGF 21未处理组相比，FGF 21延迟了首次室性心律失常的发作，并减弱了VF和维持的数量。体外研究也证实，FGF 21能缩短过氧化氢处理的AC 16细胞动作电位时程（APD）。在机制上，FGF 21可改善AC 16细胞的电生理功能，主要表现为挽救过氧化氢诱导的AC 16细胞钠电流（I Na）和内向整流钾（I k1）的表达和功能障碍。此外，当FGF受体被抑制时，FGF 21对NaV1.5和Kir2.1的恢复作用被消除。总之，FGF 21具有通过FGF受体介导的NaV1.5/Kir2.1通路改善跨膜离子通道重构的潜在作用，从而减少危及生命的梗死后心律失常，这为临床抗心律失常治疗提供了新的策略。
Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7–10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7–10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (I Na) and inward rectifier potassium (I k1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.
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影响因子：
29
作者：
Pan, Xuebo;Shao, Yihui;Lin, Zhuofeng
通讯作者：
Lin, Zhuofeng
影响因子：
5.5
作者：
Itoh N;Nakayama Y;Konishi M
通讯作者：
Konishi M
影响因子：
3.7
作者：
Lin Z;Wu Z;Yin X;Liu Y;Yan X;Lin S;Xiao J;Wang X;Feng W;Li X
通讯作者：
Li X
影响因子：
7
作者：
Ng, Fu Siong;Kalindjian, Jeremy M;Cooper, Simon A;Chowdhury, Rasheda A;Patel, Pravina M;Dupont, Emmanuel;Lyon, Alexander R;Peters, Nicholas S
通讯作者：
Peters, Nicholas S
影响因子：
5.8
作者：
Amoros, Irene;Dolz-Gaiton, Pablo;Delpon, Eva
通讯作者：
Delpon, Eva