Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP
Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP
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DOI：
10.1172/jci32011
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Galper, Jonas B.
中科院分区：
文献类型：
--
作者：
Park, Ho-Jin;Georgescu, Serban P.;Galper, Jonas B.
对心脏的副交感神经刺激可防止心律失常和猝死，涉及G蛋白偶联内向整流K通道GIRK 1/4的激活，并导致乙酰胆碱敏感性K+电流I-KACh。我们描述了脂质稳态、脂质敏感性转录因子SREBP-1、心脏副交感神经反应的调节和室性心律失常的发展之间的独特关系。在鸡胚心房肌细胞中，通过在脂蛋白耗尽的血清中培养来降低脂质增加了SREBP-1水平、GIRK 1表达和I-KACh激活。SREBP-1对GIRK 1启动子的调控和降脂作用依赖于与2个串联甾醇反应元件和上游E-box基序的相互作用。显性负性SREBP-1（DN-SREBP-1）的表达逆转了降脂作用对I-KACh和GIRK 1的影响。在SREBP-1基因敲除小鼠中，与WT相比，心脏对副交感神经刺激的反应和GIRK 1的表达均降低。SREBP-1基因敲除小鼠心房肌细胞中的I-KACh被SREBP-1表达刺激。心肌梗死后，SREBP-1基因敲除小鼠发生室性心动过速的可能性是WT小鼠的两倍。这些结果表明脂质代谢和副交感神经反应之间的关系可能在心律失常发生中发挥作用。
Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein-coupled inward rectifying K channel GIRK1/4 and results in an acetylcholine-sensitive K+ current, I-KACh. We describe a unique relationship between lipid homeostasis, the hpid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and I-KACh activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif Expression of dominant negative SREBP-1 (DN-SREBP-1) reversed the effect of lipid lowering on I-KACh and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. I-KACh, attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis.