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Published on: June 3, 2018
Fibroblast Growth Factor 21 Ameliorates NaV1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes
Jiamin Li1,2, Yuanshi Li3, Yining Liu1,2
1The Department of Pharmacology and State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin, China.
Abstract:
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.
Insights
Fibroblast growth factor 21 (FGF21) levels increase after myocardial infarction (MI), and FGF21 treatment reduces ventricular arrhythmias in animal models. FGF21 ameliorates ion channel dysfunction, offering potential antiarrhythmic therapy post-MI.
Area of Science:
- Cardiology
- Endocrinology
- Molecular Biology
Background:
- Lethal ventricular arrhythmias post-myocardial infarction (MI) are a major cause of death.
- Fibroblast growth factor 21 (FGF21), an endocrine regulator, influences glucose and lipid metabolism and shows cardiovascular benefits.
- The role of FGF21 in post-MI arrhythmias in humans remains uninvestigated.
Purpose of the Study:
- To investigate the pharmacological effects of FGF21 on cardiomyocytes following MI in humans.
- To determine FGF21 levels in patients with acute MI and arrhythmias.
- To evaluate FGF21's antiarrhythmic potential in preclinical models.
Main Methods:
- Serum FGF21 levels were measured using ELISA in patients with acute MI and healthy volunteers.
- Two arrhythmia models were established: ischemic (MI rat) and non-ischemic (ouabain-induced guinea pig).
- In vitro studies used hydrogen peroxide-treated AC16 cells to assess FGF21's effects on electrophysiology and ion channels (NaV1.5, Kir2.1).
Main Results:
- Serum FGF21 levels were elevated on day 1 post-MI, returning to normal by days 7-10.
- rhbFGF21 treatment significantly reduced the incidence and duration of ischemic arrhythmias in rats.
- FGF21 delayed ventricular arrhythmias and attenuated fibrillation in guinea pigs, and shortened action potential duration in AC16 cells by restoring NaV1.5 and Kir2.1 function via FGF receptors.
Conclusions:
- FGF21 levels increase acutely after MI in humans.
- FGF21 exhibits significant antiarrhythmic effects in both ischemic and non-ischemic arrhythmia models.
- FGF21 ameliorates post-MI arrhythmias by restoring cardiac ion channel function through the NaV1.5/Kir2.1 pathway, presenting a novel therapeutic strategy.
