Abstract
Aims: To investigate the role of KCa3. 1 inhibition in macrophage pro-inflammatory polarization and vulnerability to atrial fibrillation (AF) in a canine model with prolonged rapid atrial pacing.Materials and Methods: Twenty beagle dogs (weighing 8–10 kg) were randomly assigned to a sham group (n = 6), pacing group (n = 7) and pacing+TRAM-34 group (n = 7). An experimental model of AF was established by rapid pacing. TRAM-34 was administered to the Pacing+TRAM-34 group by slow intravenous injection (10 mg/kg), 3 times each day. After 7 days of pacing, the electrophysiology was measured in vivo. The levels of interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), CD68, c-Fos, p38, and NF-κB p65 in both atriums were measured by Western blotting, and the levels of inducible nitric oxide synthase (iNOS) and arginase1 (Arg-1) were measured by real-time PCR. Macrophage and KCa3.1 in macrophage in the atrium were quantized following double labeled immunofluorescent.Results: Greater inducibility of AF, an extended duration of AF and lower atrial effective refractory period (AERP) were observed in the pacing group compared with those in the sham group. Both CD68-labeled macrophage and the expression of KCa3.1 in macrophage were elevated in the pacing group and inhibited by TRAM-34, led to higher iNOS expression, lower Arg-1 expression, elevated levels of IL-1β, MCP-1, and TNF-α in the atria, which could be reversed by TRAM-34 treatment (all P < 0.01). KCa3.1 channels were possibly activated via the p38/AP-1/NF-κB signaling pathway.Conclusions: Inhibition of KCa3.1 suppresses vulnerability to AF by attenuating macrophage pro-inflammatory polarization and inflammatory cytokine secretion in a canine model with prolonged rapid atrial pacing.
Highlights
Greater inducibility of atrial fibrillation (AF), an extended duration of AF and lower atrial effective refractory period (AERP) were observed in the pacing group compared with those in the sham group. Both CD68-labeled macrophage and the expression of KCa3.1 in macrophage were elevated in the pacing group and inhibited by TRAM-34, led to higher inducible nitric oxide synthase (iNOS) expression, lower Arg-1 expression, elevated levels of IL-1β, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in the atria, which could be reversed by TRAM-34 treatment
In previous studies we demonstrated that KCa3.1 inhibited by TRAM-34 completely inhibited the induction of AF and prolonged the decline in AERP in canines with rapid atrial pacing
Of dogs after prolonged rapid atrial pacing, and down-regulated by TRAM-34; [2] inhibition of KCa3.1 channels decreased the vulnerability to AF after prolonged rapid atrial pacing and attenuated macrophage pro-inflammatory polarization and inflammation; [3] the effects of inhibition of KCa3.1 on AF vulnerability are probably associated with macrophage activation and the pro-inflammatory p38 MAPK/AP-1/NF-κB
Summary
Twenty beagle dogs (weighing 8–10 kg) were randomly assigned to a sham group (n = 6), pacing group (n = 7) and pacing+TRAM-34 group (n = 7). TRAM-34 was administered to the Pacing+TRAM-34 group by slow intravenous injection (10 mg/kg), 3 times each day. After 7 days of pacing, the electrophysiology was measured in vivo. Beagles (males, weighing 8–10 kg, 15 ± 2 months old) were maintained and bred in the Animal Experimental Center of Renmin Hospital at Wuhan University. Twenty beagles were randomly assigned to three groups. The control group consisted of six canines in which pacemakers were implanted under sterile conditions without atrial pacing. The pacing group consisted of seven canines in which implanted pacemakers provided continuous atrial pacing (450 beats/min) for 7 days.
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