RESUMEN
Sympathetic hyperinnervation is the leading cause of fatal ventricular arrhythmia (VA) after myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly through degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role of oxytocin (OT) in stabilizing cardiac mast cells and improving sympathetic innervation in rats. MI was induced by coronary artery ligation. Western blotting, immunofluorescence, and toluidine staining of mast cells were performed to determine the expression and location of target protein. Mast cells accumulated significantly in peri-infarcted tissues and were present in a degranulated state. They expressed OT receptor (OTR), and OT infusion reduced the number of degranulated cardiac mast cells post-MI. Sympathetic hyperinnervation was attenuated as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post-MI, the arrhythmia score of programmed electrical stimulation was higher in vehicle-treated rats with MI than in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Further in vivo studies on OTR-deficient mice showed worsening mast cell degranulation and worsening sympathetic innervation. OT pretreatment inhibited cardiac mast cell degranulation post-MI and prevented sympathetic hyperinnervation, along with mast cell stabilization via the PI3K/Akt pathway. SIGNIFICANCE STATEMENT: This is the first study to elucidate the role and mechanism of oxytocin (OT) in inflammatory-sympathetic communication mediated sympathetic hyperinnervation after myocardial infarction (MI), providing new approaches to prevent fatal arrhythmias.
Asunto(s)
Degranulación de la Célula , Mastocitos , Infarto del Miocardio , Oxitocina , Ratas Sprague-Dawley , Receptores de Oxitocina , Sistema Nervioso Simpático , Animales , Oxitocina/farmacología , Oxitocina/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratas , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Masculino , Degranulación de la Célula/efectos de los fármacos , Receptores de Oxitocina/metabolismo , Receptores de Oxitocina/antagonistas & inhibidores , Ratones , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/etiologíaRESUMEN
Sodium and potassium channels, especially Nav1.5 and Kir2.1, play key roles in the formation of action potentials in cardiomyocytes. These channels interact with, and are regulated by, synapse-associated protein 97 (SAP97). However, the regulatory role of SAP97 in myocyte remains incompletely understood. Here, we investigate the function of SAP97 phosphorylation in the regulation of Nav1.5 and Kir2.1 channel complexes and the upstream regulation of SAP97. We found that SAP97 is phosphorylated by casein kinase II (CK2) in vitro. In addition, transfection of casein kinase 2 interacting protein-1 (CKIP-1) into cardiomyocytes to drive CK2 from the nucleus to the cytoplasm, increased SAP97 phosphorylation and Nav1.5 and Kir2.1 current activity. These findings demonstrated that CKIP-1 modulates the subcellular translocation of CK2, which regulates Nav1.5 and Kir2.1 channel complex formation and activity in cardiomyocytes.
Asunto(s)
Quinasa de la Caseína II , Miocitos Cardíacos , Canal de Sodio Activado por Voltaje NAV1.5 , Canales de Potasio de Rectificación Interna , Miocitos Cardíacos/metabolismo , Quinasa de la Caseína II/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Potasio de Rectificación Interna/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/genética , Animales , Ratas , Fosforilación , Transporte de Proteínas , Humanos , Proteínas Portadoras/metabolismo , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Paeonol is a representative active ingredient of the traditional Chinese medicinal herbs Cortex Moutan, which has a well-established cardioprotective effect on ischemic heart disease. However, there is little evidence of the protective effect of paeonol, and its pharmacological mechanism is also unclear. This study aims to explore the protective effect and mechanism of Paeonol on myocardial infarction rat and hypoxic H9c2 cells. METHODS: Myocardial ischemia/reperfusion (I/R) was induced by occlusion of the left anterior descending coronary artery for 1â¯h followed by 3â¯h of reperfusion, and then gavage with Paeonol for 7 days. H9c2 cells were applied for the in vitro experiments and hypoxia/reoxygenation (H/R) model was established. CKIP-1 expression was evaluated by qPCR and western blot. The expression of genes involved in apoptosis, inflammation and ion channel was measured by western blot. The currents levels of Nav1.5 and Kir2.1 were measured by whole-cell patch-clamp recording. RESULTS: CKIP-1 expression was decreased in H/R-induced H9c2 cells, which was inversely increased after Paeonol treatment. Paeonol treatment could increase the viability of H/R-induced H9c2 cells and diminish the apoptosis and inflammation of H/R-induced H9c2 cells, while si-CKIP-1 treatment inhibited the phenomena. Moreover, the currents levels of Nav1.5 and Kir2.1 were reduced in H/R-induced H9c2 cells, which were inhibited after Paeonol treatment. Intragastric Paeonol can reduce the ventricular arrhythmias in rats with myocardial infarction. CONCLUSIONS: The protective effects of Paeonol on myocardial infarction rats and hypoxic H9c2 cells were achieved by up-regulating CKIP-1.
Asunto(s)
Acetofenonas , Hipoxia de la Célula , Regulación hacia Arriba , Acetofenonas/farmacología , Animales , Ratas , Regulación hacia Arriba/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Canales Iónicos/metabolismo , Canales Iónicos/genética , Apoptosis/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Ratas Sprague-DawleyRESUMEN
Background: Atrial fibrillation (AF) is one of the most common form of arrhythmia. Previous studies have shown a link between AF and mental illness. However, the causal relationship between mental illness and AF remains unclear. The purpose of this study was to investigate the bidirectional causal relationship between borderline personality disorder (BPD) and AF. Method: We used the bidirectional Two-sample Mendelian randomization (TSMR) method to evaluate the causal relationship between BPD and AF. Instrumental variables associated with BPD were derived from a genome-wide association study involving 214,816 Europeans (2,637 cases and 212,179 controls). We then obtained atrial fibrillation data from the GWAS meta-analysis (60,620 cases and 970,216 controls). The TSMR analyses were performed in five methods, namely fixed-effect inverse-variance weighted (IVW) methodãrandom-effect IVW method, MR Egger regression method, Weighted median method and Simple mode method. Several sensitivity analyses are used to test the robustness of positive results. Results: The fixed-effect inverse-variance weighted model [Odds ratio (OR), 1.033, 95% confidence interval (CI), 1.011-1.056, P = 0.0031], random-effect inverse-variance weighted model (OR, 1.033; 95%CI, 1.005-1.062; P = 0.0191) and Weighted median (OR, 1.034; 95%CI, 1.002-1.068; P = 0.0394) all showed that genetically predicted BPD was associated with an increased risk of AF. Sensitivity analysis using other MR Methods, including the MR-Egger intercept, MR-Presso method, and leave-one-out analyses, showed that the results were robust. In reverse MR analysis, there was no causal relationship of AF on BPD. Conclusion: Our study provides a causal relationship between BPD and AF. This means that patients with BPD should be monitored for the occurrence of AF. Early screening and proper management of BPD may show anti-arrhythmic benefits.