Abrogation of CC Chemokine Receptor 9 Ameliorates Ventricular Electrical Remodeling in Mice After Myocardial
Yan Huang1,2,3, Hua-Sheng Ding1,2,3, Tao Song1,2,3
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Insights
CC chemokine receptor 9 (CCR9) knockout prevents electrical remodeling after myocardial infarction (MI) by normalizing ion currents and calcium homeostasis. This suggests CCR9 is a potential therapeutic target for treating MI-induced arrhythmias.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Myocardial infarction (MI) causes significant structural and electrical remodeling in the heart.
- CC chemokine receptor 9 (CCR9) plays a role in inflammatory cell recruitment post-MI.
- Previous research indicated CCR9 knockout improves structural remodeling after MI.
Purpose of the Study:
- To investigate the influence of CCR9 on electrical remodeling following MI.
- To explore CCR9 as a potential therapeutic target for improving MI prognosis.
Main Methods:
- Mice models with and without CCR9 knockout were subjected to MI or sham procedures.
- Whole-cell patch clamp electrophysiology recorded action potential duration (APD) and ion currents (ICaL, Ito).
- Confocal microscopy assessed calcium transients and sarcoplasmic reticulum (SR) calcium content.
- Multielectrode array (MEA) measured ventricular conduction velocity.
- Western blot analyzed connexin 43 expression.
Main Results:
- MI induced prolonged APD90, increased ICaL, and decreased Ito, which were attenuated by CCR9 knockout.
- CCR9 knockout reversed MI-induced reductions in calcium transient and SR calcium content.
- Conduction velocity was significantly improved in CCR9 knockout mice post-MI.
- Connexin 43 expression, reduced by MI, was improved with CCR9 knockout.
Conclusions:
- CCR9 knockout prevents MI-induced electrical remodeling by normalizing ion currents, calcium handling, and gap junction expression.
- These effects help maintain normal APD and cardiac conduction.
- CCR9 emerges as a promising therapeutic target for managing MI-related arrhythmias.
Abstract:
Introduction: Myocardial infarction (MI) triggers structural and electrical remodeling. CC chemokine receptor 9 (CCR9) mediates chemotaxis of inflammatory cells in MI. In our previous study, CCR9 knockout has been found to improve structural remodeling after MI. Here, we further investigate the potential influence of CCR9 on electrical remodeling following MI in order to explore potential new measures to improve the prognosis of MI. Methods and Results: Mice was used and divided into four groups: CCR9+/+/Sham, CCR9-/-/Sham, CCR9+/+/MI, CCR9-/-/MI. Animals were used at 1 week after MI surgery. Cardiomyocytes in the infracted border zone were acutely dissociated and the whole-cell patch clamp was used to record action potential duration (APD), L-type calcium current (I ) and transient outward potassium current (I ). Calcium transient and sarcoplasmic reticulum (SR) calcium content under stimulation of Caffeine were measured in isolated cardiomyocytes by confocal microscopy. Multielectrode array (MEA) was used to measure the conduction of the left ventricle. The western-blot was performed for the expression level of connexin 43. We observed prolonged APD90, increased I and decreased I following MI, while CCR9 knockout attenuated these changes (APD90: 50.57 ± 6.51 ms in CCR9-/-/MI vs. 76.53 ± 5.98 ms in CCR9+/+/MI, p < 0.05; I : -13.15 ± 0.86 pA/pF in CCR9-/-/MI group vs. -17.05 ± 1.11 pA/pF in CCR9+/+/MI, p < 0.05; I : 4.01 ± 0.17 pA/pF in CCR9-/-/MI group vs. 2.71 ± 0.16 pA/pF in CCR9+/+/MI, p < 0.05). The confocal microscopy results revealed CCR9 knockout reversed the calcium transient and calcium content reduction in sarcoplasmic reticulum following MI. MEA measurements showed improved conduction velocity in CCR9-/-/MI mice (290.1 ± 34.47 cm/s in CCR9-/-/MI group vs. 113.2 ± 14.4 cm/s in CCR9+/+/MI group, p < 0.05). Western-blot results suggested connexin 43 expression was lowered after MI while CCR9 knockout improved its expression. Conclusion: This study shows CCR9 knockout prevents the electrical remodeling by normalizing ion currents, the calcium homeostasis, and the gap junction to maintain APD and the conduction function. It suggests CCR9 is a promising therapeutic target for MI-induced arrhythmia, which warrants further investigation.
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