Abrogation of CC Chemokine Receptor 9 Ameliorates Ventricular Electrical Remodeling in Mice After Myocardial Infarction

Figures

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  Figure 1. CCR9 knock down inhibits APD prolongation following MI. (A) Representive action potential recordings in mouse ventricular myocytes from each group. (B) Quantified analysis of APD90 in CCR9+/+ and CCR9−/− mice with sham operation or MI surgery at 1 week (*p < 0.05 vs. CCR9+/+/Sham, #p < 0.05 vs. CCR9+/+/MI).

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  Figure 2. CCR9 knockoutattenuates MI-induced calcium current increasing and reduction of transient outward potassium current after MI. (A) Representive raw traces of ICa,L in mouse ventricular myocytes from each group. (B) Normalized current–voltage relationship for ICa,L (**p < 0.01 vs. CCR9+/+/Sham, #p < 0.05 vs. CCR9+/+/MI). (C) Representive raw traces of Ito in ventricular myocytes from each group. (D) Normalized current–voltage relationship for Ito (*p < 0.05 vs. CCR9+/+/Sham, #p < 0.05 vs. CCR9+/+/MI).

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  Figure 3. CCR9 deficiency restores calcium handling after MI. (A) Representive Ca2+transients and SR Ca2+content recordings at 0.5 and 1-Hz field stimulation in mouse myocytes from each group. (B) Statistical analysis of Ca2+transient amplitude (ΔF/F0) in each groups (*p < 0.05 vs. CCR9+/+/Sham, #p < 0.05 vs. CCR9+/+/MI). (C) Quantified analysis of SR Ca2+content following 10 mM caffeine perfusion in different groups (*p < 0.05 vs. CCR9+/+/Sham, #p < 0.05 vs. CCR9+/+/MI).

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  Figure 4. CCR9 knockout improves the conduction function after MI. (A) The conduction maps of excitation in the left ventricle recorded by MEA. MI mice presented crowding isochronal, of which the crowding degree was less in the CCR9−/− MI group. (B) Heterogeneity of conduction in mice left ventricle. There was more heterogeneous in CCR9+/+/MI mice than CCR9−/−/MI mice. (C) Statistical analysis of CV in each group. CCR9 knockout increased the ventricular CV following MI. (**p < 0.01 vs. CCR9+/+/Sham, #p < 0.05 vs. CCR9+/+/MI).

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  Figure 5. CCR9 knock out preserves the expression of Cx43. (A) Western blot band of Cx43 in sham or MI mice heart tissues. (B) Cx43 expression level in each group (**p < 0.01 vs. CCR9+/+/Sham, ##p < 0.01 vs. CCR9+/+/MI).

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  Figure 6. The potential role of CCR9/CCL25 in cardiac remodeling after MI. Following MI, CCR9/CCL25 is activated. Inflammatory cells tend to distribute toward the infarct area and secrete inflammatory factors. Cytokines accelerate structural and electrical remodeling by activating cardiac fibrosis, impairing gap junction via changes in connexin 43 expression, disrupting calcium homeostasis. These pathological changes increase ectopic activity, decrease ventricular conduction and promote reentry, which are substrate for ventricular arrhythmias. Whereas, CCR9 knockout improves cardiac inflammation and fibrosis by inhibiting CCR9/CCL25 activation, as well as inflammatory cytokines chemotaxis, which maintains expression of connexin43 and electrical activity of cardiomyocytes, and preventing ventricular arrhythmias.