Abstract
BackgroundCoronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME.MethodsForty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively.ResultsWestern blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P < 0.01), indicating less severe myocardial damage and arrhythmias. The G-CSF group showed higher phosphorylated-Cx43 expression (P < 0.01 vs. CME). Those G-CSF-induced changes were reversed by A490, indicating the involvement of JAK2. G-CSFR, phosphorylated-JAK2, and phosphorylated-STAT3 protein levels were higher in the G-CSF group than in the AG490 (P < 0.01) and Sham (P < 0.05) groups.ConclusionG-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.
Highlights
Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence
Rabbit body weight declined after surgery in the CME group but not in the other groups One rabbit from the AG490 group died during the experiments, and 39 rabbits completed the study
Bodyweight at 2 weeks after surgery was significantly lower in the CME group than in the Sham (P < 0.01), granulocyte colony-stimulating factor (G-CSF) (P < 0.01), and AG490 (P < 0.05) groups (Fig. 1a)
Summary
Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME. The main cause of no-reflow or slow-reflow after PCI is coronary microembolism (CME) [3], resulting in myocardial cell necrosis and apoptosis, ventricular remodeling, malignant arrhythmia, and cardiac failure [4]. Remodeling of Cx43 and phosphorylated Cx43 (p-Cx43) distribution after ischemia is thought to cause increased anisotropy of electrical conduction and abnormal synchronization and coordination of electrical activity, leading to ventricular arrhythmia [7]. Whether Cx43 remodeling occurs after CME and increases the susceptibility to ventricular arrhythmias is not fully understood
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