MicroRNA-328参与房颤的逆向电重构
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MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation
背景与目的：临床和实验性心房颤动(AF)的一个特点是心房电重构与L型Ca2+电流的大幅度减少和动作电位持续时间的缩短有关，但microRNAs参与这一过程的可能性还未得到证实。因此，本实验旨在探究miRNAs在调节实验性房颤中的潜在作用。
1
方法：用微阵列分析miRNA转录体，并用实时逆转录聚合酶链反应(RT-PCR)对右心房快速起搏8周建立的犬房颤模型和风湿性心脏病患者的心房标本进行检测。
结果：结果显示，miR-223、miR-328和 miR-664 的表达水平上调2倍 ，而miR-101、 miR-320和 miR-499 下调至少50%。与非AF受试者相比，miR-328在犬房颤模型中上调3.9倍，在房颤患者中上调3.5倍。计算机预测表明，CACNA1C和CACNB1编码心脏L型Ca2+通道α1c-和β1亚基，两者均为miR-328的潜在作用靶点。通过腺病毒感染使犬心房强制表达miR-328，并在小鼠中通过转基因方法再现AF的表型，如增强AF易损性、减少L型Ca2+电流和缩短心房动作电位时程。用miR拮抗剂标准化miR-328水平逆转了反应条件，并且敲除内源性miR-328的基因可抑制AF易感性。Western blot证实CACNA1C和CACNB1是miR-328的同源靶基因，并通过荧光素酶活性分析证实了mir-328与L型Ca2+通道蛋白亚基表达水平之间的相互关系。
结论：miR-328可通过靶向调控L型Ca2+通道基因诱导房颤不良的心房电重构。因此，本研究揭露了AF发生的一个新的分子机制，并且表明miR-328可作为AF治疗的一个潜在靶点。
Lu Y, Zhang Y, Wang N, et al. MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation[J]Circulation 2010 Dec 07 ;122(23) DOI：10.1161/CIRCULATIONAHA.110.958967
Sbstract
Background—A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca2+ current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF.
Methods and Results—The miRNA transcriptome was analyzed by microarray and verified by real-time reversetranscription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223,miR-328, and miR-664 were found to be upregulated by 2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca2 channel 1c- and 1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca2 current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca2 channel protein subunits.
Conclusions—miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca2 channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF.
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