Project Details
Description
Aims: Macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, is highly expressed in patients with atrial fibrillation (AF). Inflammation increases the risk of AF and is primarily triggered by pulmonary vein (PV) arrhythmogenesis. This study investigated whether MIF can modulate the electrical activity of the PV and examined the underlying mechanisms of MIF.
Methods: A conventional microelectrode, a whole-cell patch clamp, Western blotting, and immunofluorescent confocal microscopy were used to investigate electrical activity, calcium (Ca2+) regulation, protein expression, ionic currents, and cytosolic reactive oxygen species (ROS) in rabbit PV tissue and isolated single cardiomyocytes with and without MIF incubation (100 ng/mL, treated for 6 h).
Results: The MIF (100 ng/mL)-treated PV tissue (n = 8) demonstrated a faster beating rate (1.8 ± 0.2 vs 2.6 ± 0.1 Hz, P < 0.05), higher incidence of triggered activity (12.5% vs 100%, P < 0.05), and premature atrial beat (0% vs 100%, P < 0.05) than the control PV tissue (n = 8). Compared with the control PV cardiomyocytes, MIF-treated single PV cardiomyocytes had larger Ca2+ transients (0.6 ± 0.1 vs 1.0 ± 0.1, F/F0, P < 0.05), sarcoplasmic reticulum Ca2+ content (0.9 ± 0.20 vs 1.7 ± 0.3 amol/pF, P < 0.05), and cytosolic ROS (146.8 ± 5.3 vs 163.7 ± 3.8, F/F0, P < 0.05). Moreover, MIF-treated PV cardiomyocytes exhibited larger late sodium currents (INa-Late¬), L-type Ca2+ currents, and Na+/Ca2+ exchanger currents than the control PV cardiomyocytes. KN93 (a selective CaMKII blocker, 1 μM), ranolazine (a INa-Late inhibitor, 10 μM) and N-MPG (ROS inhibitor, 10 mM) reduced the beating rates and the incidence of triggered activity and premature captures in the MIF-treated PV tissue.
Conclusions: MIF increased PV arrhythmogenesis through Na+ and Ca2+ dysregulation through the ROS activation of CaMKII signaling, which may contribute to the genesis of AF during inflammation. Anti-CaMKII treatment may reverse PV arrhythmogenesis. Our results clearly reveal a key link between MIF and AF and offer a viable therapeutic target for AF treatmen
Methods: A conventional microelectrode, a whole-cell patch clamp, Western blotting, and immunofluorescent confocal microscopy were used to investigate electrical activity, calcium (Ca2+) regulation, protein expression, ionic currents, and cytosolic reactive oxygen species (ROS) in rabbit PV tissue and isolated single cardiomyocytes with and without MIF incubation (100 ng/mL, treated for 6 h).
Results: The MIF (100 ng/mL)-treated PV tissue (n = 8) demonstrated a faster beating rate (1.8 ± 0.2 vs 2.6 ± 0.1 Hz, P < 0.05), higher incidence of triggered activity (12.5% vs 100%, P < 0.05), and premature atrial beat (0% vs 100%, P < 0.05) than the control PV tissue (n = 8). Compared with the control PV cardiomyocytes, MIF-treated single PV cardiomyocytes had larger Ca2+ transients (0.6 ± 0.1 vs 1.0 ± 0.1, F/F0, P < 0.05), sarcoplasmic reticulum Ca2+ content (0.9 ± 0.20 vs 1.7 ± 0.3 amol/pF, P < 0.05), and cytosolic ROS (146.8 ± 5.3 vs 163.7 ± 3.8, F/F0, P < 0.05). Moreover, MIF-treated PV cardiomyocytes exhibited larger late sodium currents (INa-Late¬), L-type Ca2+ currents, and Na+/Ca2+ exchanger currents than the control PV cardiomyocytes. KN93 (a selective CaMKII blocker, 1 μM), ranolazine (a INa-Late inhibitor, 10 μM) and N-MPG (ROS inhibitor, 10 mM) reduced the beating rates and the incidence of triggered activity and premature captures in the MIF-treated PV tissue.
Conclusions: MIF increased PV arrhythmogenesis through Na+ and Ca2+ dysregulation through the ROS activation of CaMKII signaling, which may contribute to the genesis of AF during inflammation. Anti-CaMKII treatment may reverse PV arrhythmogenesis. Our results clearly reveal a key link between MIF and AF and offer a viable therapeutic target for AF treatmen
| Status | Finished |
|---|---|
| Effective start/end date | 9/1/22 → 8/31/23 |
Keywords
- Targeting Toll-like Receptor 4 Signaling in Atrial Arrhythmogenesis via electrical and structural modulation
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