Fibroblast Growth Factor 1 Reduces Pulmonary Vein and Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis

Figures

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  Figure 1. Effects of fibroblast growth factor 1 (FGF1) on the electrocardiography (ECG) of rabbits and electrophysiological characteristics of pulmonary vein (PV) and left atrial (LA) tissues. (A) Control rabbits (N = 6) had a faster regular rhythm than that observed in FGF1 (3 μg/kg)-treated rabbits (N = 6). (B) Tracings and scatter plots illustrated that PV tissues of FGF1 (3 μg/kg)-treated rabbits (N = 6) had a slower spontaneous activities with a decreased early and late diastolic depolarization than that observed in control rabbits (N = 5). (C) Examples and scatter plots of the action potential (AP) morphology from LA tissues under regular pacing (2 Hz) in the control (N = 7) and FGF1 (3 μg/kg)-treated rabbits (N = 6). RMP indicates resting membrane potential, APA indicates AP amplitude, APD20, APD50, and APD90 indicate that AP duration at 20, 50, and 90% repolarization of the amplitude, respectively, EDD indicates early diastolic depolarization, LDD indicates late diastolic depolarization, dV/dtmax indicates maximum upstroke velocity.

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  Figure 2. Effect of isoproterenol (ISO) on spontaneous activity of left atrium (LA) and pulmonary vein (PV) tissues with or without fibroblast growth factor 1 (FGF1) treatment. (A) Tracings and scatter plots of ISO (1 μM)-induced changing PV spontaneous activities in rabbits with (N = 7) or without (N = 6) FGF1 (3 μg/kg) treatment. (B) The upper panel shows the representative tracings and scatter plots of LA action potential morphology under regular pacing (2 Hz) in the control and FGF1 (3 μg/kg)-treated rabbits (both N = 6). The lower panel shows the tracings and incidence of LA burst firing under rapid atrial pacing (20 Hz) and ISO (1 μM) infusion in the control and FGF1 (3 μg/kg)-treated rabbits (both N = 6).

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  Figure 3. Effect of fibroblast growth factor 1 (FGF1) on spontaneous activities, sodium (Na+) current (INa), late Na+ current (INa−Late), sodium–calcium exchanger (NCX), and L-type calcium current (ICa−L) of pulmonary vein (PV) myocytes. (A) Examples of current traces and scatter plots of beating rate in the control (N = 7) and FGF1 (1 and 10 ng/mL)-treated PV myocytes (both N = 10). (B) Examples of current traces and scatter plots of INa in the control (N = 8) and FGF1 (10 ng/mL)-treated PV myocytes (N = 9). (C) Examples of current traces and scatter plots of INa−Late in the control (N = 8) and FGF1 (10 ng/mL)-treated PV myocytes (N = 14). (D) Examples of current traces and I–V relationship of NCX in the control (N = 7) and FGF1 (10 ng/mL)-treated PV myocytes (N = 9). (E) Examples of current traces and I–V relationship of ICa−L in the control (N = 7) and FGF1 (10 ng/mL)-treated PV myocytes (both N = 9). *P < 0.05.

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  Figure 4. Effect of fibroblast growth factor 1 (FGF1) on action potential morphology, transient outward potassium current (Ito) and rapid delayed rectifier potassium current (IKr−tail), late sodium current (INa−Late), sodium–calcium exchanger (NCX), and L-type calcium current (ICa−L) in left atrium (LA) myocytes. (A) Examples of current traces, scatter plots of electrophysiological characteristics and dose response curves on the control (N = 8) and FGF1 (1 and 10 ng/mL)-treated LA myocytes (N = 10 and 8, respectively). (B) Examples of current traces and I–V relationship of Ito in the control (N = 9) and FGF1 (10 ng/mL)-treated LA myocytes (N = 10). (C) Examples of current traces and I–V relationship of IKr−tail in the control (N = 12) and FGF1 (10 ng/mL)-treated LA myocytes (N = 10). (D) Examples of current traces and scatter plots of INa−Late in the control (N = 9) and FGF1 (10 ng/mL)-treated LA myocytes (N = 11). (E) Examples of current traces and I–V relationship of NCX in the control and FGF1 (10 ng/mL)-treated LA myocytes (both N = 6). (F) Examples of current traces and I–V relationship of ICa−L in the control and FGF1 (10 ng/mL)-treated LA myocytes (both N = 10). *P < 0.05.

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  Figure 5. Effect of fibroblast growth factor 1 (FGF1) on intracellular calcium (Ca2+) homeostasis, reactive oxygen species (ROS) and cytosol malondialdehyde (MDA) in pulmonary vein (PV) and left atrium (LA) myocytes. (A) Examples of tracings and scatter plots of Ca2+ transients in the control and FGF1 (10 ng/mL)-treated PV (N = 25 and 17, respectively), and LA (N = 9 and 14, respectively), myocytes. (B) Examples and scatter plots of cellular levels of ROS in the control and FGF1 (10 ng/mL)-treated PV (N = 11 and 10, respectively), and LA (N = 12 and 15, respectively), myocytes. (C) Scatter plots of cytosol MDA in control and FGF1 (10 ng/mL)-treated PV (each N = 7) and LA (each N = 7) tissues.

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  Figure 6. Effect of protein kinase C epsilon inhibitor (εV1-2) on transient outward potassium current (Ito) and rapid delayed rectifier potassium current (IKr−tail) in FGF1-treated left atrial (LA) myocytes, and on late sodium current (INa−Late) in FGF1-treated pulmonary vein (PV) myocytes. (A) Examples of current traces and I–V relationship of Ito in FGF1 (10 ng/mL)-treated LA myocytes with or without εV1-2 (200 nM) (each N = 7). (B) Examples of current traces and I–V relationship of IKr−tail in FGF1 (10 ng/mL)-treated LA myocytes with (N = 8) or without (N = 9) εV1-2 (200 nM). (C) Examples of current traces and average data of INa−Late in FGF1 (10 ng/mL)-treated PV myocytes with (N = 8) or without (N = 9) εV1-2 (200 nM).