小鼠高脂饮食性肥胖诱发自发性心律失常并增加兰尼碱受体活性
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High-Fat-Diet-Induced Obesity Produces Spontaneous Ventricular Arrhythmias and Increases the Activity of Ryanodine Receptors in Mice
背景
心律失常是心源性猝死的最常见原因，在肥胖体质中发生较高。兰尼碱受体（RyR2）活性及肌质网的钙通道异常可产生心律失常。肥胖产生的氧化应激及RyR2是氧化还原敏感性通道。
方 法
我们研究了肥胖小鼠RyR2活性是否发生了改变。高脂饮食(HFD)小鼠，喂养8周后变肥胖，其心律失常的发生显著增加。从肥胖小鼠心脏分离的单个RyR2比对照组更加活跃。
结 果
在分子水平，HFD小鼠的RyR2游离巯基残基显著减少，表明氧化还原修饰引起更高的RyR2活性。含罗布麻宁的饮用水抑制了HFD小鼠出现室性心律失常，并使蛋白质的游离巯基残基的活性和含量标准化。HFD增加心脏的NOX4的表达，这是NADPH氧化酶的同种类型。
结 论
我们的结果提示HFD通过氧化应激增加RyR2活性，使得心律失常更容易发生。
原始文献摘要
Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was
altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias.
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