来自哈尔滨医科大学药理学系与心脏血管研究院等处的研究人员首次发现心房颤动发生的新机制，并观察到一种小RNA：miRNA-328能调控了心房颤动的发生。这将对心脏疾病的预防、诊断、治疗以及生物医药产业的发展起到重要推动作用。这一研究成果公布在心血管领域权威杂志《Circulation》上。

领导这一研究的是哈尔滨医科大学的杨宝峰教授，其早年毕业于同济医科大学，曾于日本筑波Eisai研究所和加拿大蒙特利尔心脏病研究所进行研究工作，主要的研究方向是抗心律失常和离子通道领域，曾首次于国内外提出抗心律失常药物作用最佳靶点学说，并被编入本科生、研究生国家统编教材。2009年入选中国工程院院士。

miRNAs是一种21－25nt长的单链小分子RNA，对于它的研究起始于时序调控小RNA（stRNAs），由于miRNAs在物种进化中相当保守，在植物、动物和真菌中发现的miRNAs只在特定的组织和发育阶段表达，而且这种特异性和时序性，决定了组织和细胞的功能特异性，表明miRNA在细胞生长和发育过程的调节过程中起多种作用，因此miRNA的研究受到了生物学家的广泛关注。

目前对miRNA功能的理解主要依赖于其在组织特异性或者发育阶段特异性表达，以及其进化保守性方面，因此主要受限在发育调控和癌症形成的研究。在这篇最新的文章中，研究人员发现了miRNA-328能调控心房颤动的发生，这是国内外第一次从微小核苷酸领域分子水平上解读心房颤动的发生机制。

研究人员发现心房颤动的患者微小核苷酸-328显著升高，且升高程度与发病程度密切相关。为了确定微小核苷酸-328在房颤中的作用，杨宝峰院士、王志国教授、吕延杰教授与该校转基因动物中心主任高旭教授、张凤民教授以及哈医大一院心内科李悦教授合作，在国际上首次建立心脏特定微小核苷酸（1，26，328亚型）过表达转基因鼠和微小核苷酸功能敲减小鼠（328亚型）模型，发现微小核苷酸-328的过表达可以诱发小鼠房颤的发生，而微小核苷酸-328功能敲减小鼠或给予腺病毒连接的微小核苷酸-328反义寡核苷酸则可减轻房颤的发生。为进一步解释微小核苷酸-328升高诱发心房颤动的靶点，课题组运用多种实验手段证明，抑制微小核苷酸-328可减少房颤的发生。

这一研究通过大量离体、在体动物实验和临床观察，最终确定微小核苷酸-328为心房颤动发生的关键调控分子，并锁定了一个可以治疗房颤的新靶点。这是国内外第一次从微小核苷酸领域分子水平上解读心房颤动的发生机制。有关专家认为，该项研究将对心脏疾病的预防、诊断、治疗以及生物医药产业的发展起到重要推动作用。

原文摘要：

MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation.

Background- A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca(2+) 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 reverse-transcription 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 Ca(2+) channel α1c- and β1 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 Ca(2+) 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 Ca(2+) channel protein subunits. Conclusions- miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca(2+) channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF.