RESUMEN
KCNE ß-subunits play critical roles in modulating cardiac voltage-gated potassium channels. Among them, KCNE1 associates with KCNQ1 channel to confer a slow-activated IKs current, while KCNE2 functions as a dominant negative modulator to suppress the current amplitude of KCNQ1. Any anomaly in these channels will lead to serious myocardial diseases, such as the long QT syndrome (LQTS). Trafficking defects of KCNE1 have been reported to account for the pathogenesis of LQT5. However, the molecular mechanisms underlying KCNE forward trafficking remain elusive. Here, we describe an arginine/lysine-based motif ([R/K](S)[R/K][R/K]) in the proximal C-terminus regulating the endoplasmic reticulum (ER) export of KCNE1 and KCNE2 in HEK293 cells. Notably, this motif is highly conserved in the KCNE family. Our results indicate that the forward trafficking of KCNE2 controlled by the motif (KSKR) is essential for suppressing the cell surface expression and current amplitude of KCNQ1. Unlike KCNE2, the motif (RSKK) in KCNE1 plays important roles in modulating the gating of KCNQ1 in addition to mediating the ER export of KCNE1. Furthermore, truncations of the C-terminus did not reduce the apparent affinity of KCNE2 for KCNQ1, demonstrating that the rigid C-terminus of KCNE2 may not physically interact with KCNQ1. In contrast, the KCNE1 C-terminus is critical for its interaction with KCNQ1. These results contribute to the understanding of the mechanisms of KCNE1 and KCNE2 membrane targeting and how they coassemble with KCNQ1 to regulate the channels activity.
Asunto(s)
Retículo Endoplásmico/metabolismo , Canal de Potasio KCNQ1/metabolismo , Canales de Potasio con Entrada de Voltaje/química , Canales de Potasio con Entrada de Voltaje/metabolismo , Secuencias de Aminoácidos , Arginina/metabolismo , Retículo Endoplásmico/química , Retículo Endoplásmico/genética , Células HEK293 , Humanos , Canal de Potasio KCNQ1/química , Canal de Potasio KCNQ1/genética , Lisina/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Transporte de ProteínasRESUMEN
BACKGROUND AND AIM: Many studies have reported that genetic variants correlate with higher risk for coronary artery disease (CAD) or in-stent restenosis (ISR) after bare metal stent (BMS) implantation. However, there is limited data assessing the impact of these variants on ISR in patients treated with drug-eluting stent (DES). The purpose of this study was to investigate the effects of genetic risk factors on ISR in Chinese Han patients treated with DES. METHODS: A total of 425 patients with a diagnosis of CAD who underwent successful revascularization in native coronary arteries with DES were included in this retrospective study. Genotyping was performed on six single nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase gene (eNOS), the angiotensin converting enzyme gene (ACE), the angiotensin II type 1 receptor gene (AT1R), the transforming growth factor beta gene (TGF-ß), and the vascular endothelial growth factor gene (VEGF). Quantitative coronary angiography (QCA) was performed during the follow-up period to detect ISR. Logistic regression models were used to test for association. RESULTS: Fifty-four patients (12.7%) developed ISR during the follow-up period. Of the six analyzed SNPs, the frequency of the C allele of T786C polymorphism in eNOS was significantly higher in the ISR group (22.2%) compared to the non-ISR group (12.7%) (p<0.01). In the ISR group, the frequency of the TT, TC, and CC genotypes was 61.1%, 33.3%, and 5.6%, respectively, and in the non-ISR group, the frequencies were 76.8%, 21.0%, and 2.2%, respectively. The multivariable analysis adjusted for potential confounders and revealed that the T786C polymorphism increased the risk of ISR in both additive and dominant models with odds ratios of 1.870 (95% confidence interval [CI]: 1.079-3.240, p = 0.03) and 2.045 (95% CI: 1.056-3.958, p = 0.03), respectively. CONCLUSION: The eNOS T786C polymorphism was associated with ISR in Chinese Han patients treated with DES. Genotyping may be helpful to identify patients with higher risks of ISR after DES implantation.
Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Reestenosis Coronaria/genética , Stents Liberadores de Fármacos/efectos adversos , Óxido Nítrico Sintasa/genética , Adulto , Anciano , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/cirugía , Reestenosis Coronaria/patología , Reestenosis Coronaria/cirugía , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Stents/efectos adversosRESUMEN
OBJECTIVE: To investigate the effects of metoprolol on electrophysiology of ischemic and anoxic myocardium in diabetic rats. METHODS: Forty Sprague-Dawley (SD) rats were divided into 4 groups: diabetes group; diabetes and ablation of left sympathetic nerve group; diabetes and metoprolol group and sham group. The diabetes model was induced by intraperitoneal injection of streptozotocin (STZ, 60 mg/kg). The ventricular diastolic effective threshold (DET), effective refractive period (ERP), and Ventricular fibrillation threshold (VFT) were measured. The serum concentration of nerve growth factor (NGF) was measured. RESULTS: Metoprolol increased DET of ischemic and anoxic myocardium in diabetic rats. The ablation of the left sympathetic nerve increased VFT of diabetic rats. VFT in metoprolo group was significantly increased compared to diabetes group after ischemia. The concentrations of NGF in diabetic group and metoprolol group were higher than those in sham group. There were no difference in NGF levels between ablation of left sympathetic nerve group and sham group. CONCLUSION: The remodeling of sympathetic nerve affects the electrophysiology of ischemic myocardium of diabetic rats. Metoprolol can increase the VFT and decrease the excitation threshold of the ischemic myocardium in diabetic rats.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Corazón/fisiopatología , Metoprolol/farmacología , Isquemia Miocárdica/fisiopatología , Animales , Corazón/efectos de los fármacos , Masculino , Factor de Crecimiento Nervioso/sangre , Ratas , Ratas Sprague-Dawley , SimpatectomíaRESUMEN
CONTEXT: Newborns are subject to pain during routine invasive procedures. Pain caused by immunization injections is preventable, but remains untreated in neonates. OBJECTIVES: The purpose of the study was to compare the effectiveness of three nonpharmacological pain relief strategies on newborns' pain, physiological parameters, and cry duration before, during, and after hepatitis B intramuscular (IM) injection. METHODS: In this prospective, randomized clinical trial, we enrolled 165 newborns (gestational age, ≥36 weeks). The infants received IM injections and were randomized to three treatment groups: nonnutritive sucking (NNS), 20% oral sucrose, or routine care. Pain was measured by the Neonatal Facial Coding System, physiological signals by electrocardiogram monitors, and cry duration using a stopwatch. RESULTS: Pain was significantly lower among infants in the NNS (B=-11.27, P<0.001) and sucrose (B=-11.75, P<0.001) groups than that in controls after adjusting for time effects, infant sleep/wake state, number of prior painful experiences, and baseline pain scores. Infants in the NNS and sucrose groups also had significantly lower mean heart and respiratory rates than the controls. Cry duration of infants receiving sucrose was significantly shorter than those in the NNS (Z=-3.36, P<0.001) and control groups (Z=-7.80, P<0.001). CONCLUSION: NNS and oral sucrose can provide analgesic effects and need to be given before painful procedures as brief as a one-minute IM injection. Sucrose orally administered two minutes before injection more effectively reduced newborns' pain during injection than NNS. Both nonpharmacological methods more effectively relieved newborns' pain, stabilized physiological parameters, and shortened cry duration during IM hepatitis injection than routine care.