芦荟大黄素通过抑制MiR-1和上调IK1缓解高脂饮食导致的大鼠QT延长
Aloe-Modding Relieves High-Fat Diet Induced QT Prolongation via MiR-1 Inhibition and I K1 Up-Regulation in Rats
背景/目的：高脂饮食（HFD）导致心脏电生理重构并增加室性心律失常的风险。芦荟大黄素（AE）是一种从大黄中分离出来的蒽醌成分，与大黄素具有相似的化学结构。文献报道了大黄素对心脏疾病的保护作用。然而，AE的心脏保护特性尚不清楚。
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方法：把成年雄性Wistar大鼠随机分为三组：对照组，HFD组和AE组。对照组给予正常饮食，HFD组和AE组大鼠给予高脂饮食4周建立HFD模型。随后AE组大鼠每天胃内灌注AE 100mg/kg共6周。采用心电图监测和全细胞膜片钳技术分别检测心脏电活动、动作电位和内向整流钾电流（IK1）。给予新生大鼠心室肌细胞（NRVMs）胆固醇和/或AE。通过蛋白质印迹检测Kir2.1的蛋白质表达，并且通过实时PCR分别在体内和体外检测miR-1水平。
结果：在体实验中，AE显著缩短了由HFD大鼠延长的QT间期。此外，AE明显抑制了HFD大鼠心脏中促心律失常的miR-1.在离体实验中，AE降低了miR-1的表达水平，导致富含胆固醇的NRVMs中Kir2.1蛋白水平的增加。
结论：AE通过抑制miR-1和上调靶点Kir2.1通道改善了HFD诱导的QT间期延长。该发现提示了AE在HDF导致的心脏电生理重构中的一个新药理作用。
Abstract
Background/Aims: High-fat diet (HFD) causes cardiac electrical remodeling and increases the risk of ventricular arrhythmias. Aloe-emodin (AE) is an anthraquinone component isolated from rhubarb and has a similar chemical structure with emodin. The protective effect of emodin against cardiac diseases has been reported in the literature. However, the cardioprotective property of AE is still unknown. The present study investigated the effect of AE on HFD-induced QT prolongation in rats. Methods: Adult male Wistar rats were randomly divided into three groups: control, HFD, and AE-treatment groups. Normal diet was given to rats in the control group, high-fat diet was given to rats in HFD and AE-treatment groups for a total of 10 weeks. First, HFD rats and AE-treatment rats were fed with high-fat diet for 4 weeks to establish the
HFD model. Serum total cholesterol and triglyceride levels were measured to validate the HFD model. Afterward, AE-treatment rats were intragastrically administered with 100 mg/kg AE each day for 6 weeks. Electrocardiogram monitoring and whole-cell patch-clamp technique were applied to examine cardiac electrical activity, action potential and inward rectifier K + current (I K1 ), respectively. Neonatal rat ventricular myocytes (NRVMs) were subjected to cholesterol and/or AE. Protein expression of Kir2.1 was detected by Western blot and miR- 1 level was examined by real-time PCR in vivo and in vitro, respectively. Results: In vivo, AE significantly shortened the QT interval, action potential duration at 90% repolarization (APD 90 )
and resting membrane potential (RMP), which were markedly elongated by HFD. AE increased I K1 current and Kir2.1 protein expression which were reduced in HFD rats. Furthermore, AE significantly inhibited pro-arrhythmic miR-1 in the hearts of HFD rats. In vitro, AE decreased miR-1 expression levels resulting in an increase of Kir2.1 protein levels in cholesterol-enriched NRVMs. Conclusions: AE prevents HFD-induced QT prolongation by repressing miR-1 and upregulating its target Kir2.1. These findings suggest a novel pharmacological role of AE in HFD-induced cardiac electrical remodeling.METHODS: Retrospective charreview. RESULTS:Patients who received a single-shot regional anesthetic reported significantly more postoperative opiate consumption and requested pain medication significantly sooner than patients who received multimodal techniques of regional analgesia.CONCLUSION: This study found support for the use of multimodal analgesia techniques for optimum postoperative pain management after total knee arthroplasty.
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