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Circulation:我学者首次揭示心房颤动发生新“奥秘”

来源:科技日报 2010-12-03 19:31

由哈尔滨医科大学“重大心脏疾病基础研究”973项目首席科学家杨宝峰院士领衔的科研团队,于近期在国际上首次发现临床最为常见的心律失常类型——心房颤动发生的新机理及微小核苷酸-328调控心房颤动的发生。

课题组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。为揭开微小核苷酸-328在房颤中的“奥秘”,杨宝峰及课题组成员联手攻关,在国际上首次建立起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),发现微小核苷酸 -328的过表达能诱发出小鼠的心房颤动,而微小核苷酸-328功能敲减小鼠或给予腺病毒转染的微小核苷酸-328反义寡核苷酸,则可减轻房颤的发生。

为进一步揭秘微小核苷酸-328升高诱发心房颤动的靶点,课题组运用多种实验证明,微小核苷酸-328使编码钙通道的两个基因CACNA1C和 CACNB1蛋白表达,且L型钙电流大小也随之显著降低。相反,抑制微小核苷酸-328可减少房颤的发生。课题组通过大量离体、在体动物的实验和临床观察,最终确定微小核苷酸-328为心房颤动发生的关键调控分子,首次从微小核苷酸领域这一分子水平上解读心房颤动的发生机理,由此锁定了一个可以治疗房颤的新靶点,对心房颤动的诊治有着重大意义,为心脏疾病领域的生物医药产业的创新研发奠定了基础。(生物谷Bioon.com)

生物谷推荐原文出处:

Circulation    doi: 10.1161/CIRCULATIONAHA.110.958967

MicroRNA-328 Contributes to Adverse Electrical Remodeling in Atrial Fibrillation

Yanjie Lu, MD, PhD*; Ying Zhang, MD, PhD*; Ning Wang, MD, PhD; Zhenwei Pan, MD, PhD; Xu Gao, MD, PhD; Fengmin Zhang, MD, PhD; Yong Zhang, MD, PhD; Hongli Shan, MD, PhD; Xiaobin Luo, MSc; Yunlong Bai, MD, PhD; Lihua Sun, MD, PhD; Wuqi Song, MD, PhD; Chaoqian Xu, MD, PhD; Zhiguo Wang, PhD Baofeng Yang, MD, PhD

From the Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China) (Y.L., Y.Z., N.W., Z.P., Y.Z., H.S., X.L., Y.B., L.S., C.X., Z.W., B.Y.) and Departments of Biochemistry (X.G.) and Microbiology (F.Z., W.S.), Harbin Medical University, Harbin, PR China.

Correspondence to Zhiguo Wang, PhD, FAHA, FESC, Research Center, Montreal Heart Institute, 5000 Belanger E, Montreal, PQ H1T 1C8, QC, Canada (E-mail wz.email@gmail.com or zhiguo.wang@icm-mhi.org); or Baofeng Yang, MD, PhD, Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang 150081, PR China (E-mail yangbf@ems.hrbmu.edu.cn).

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 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 Ca2+ channel 1c- 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 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.

Key Words: arrhythmia • atrial fibrillation • gene expression • ion channels • pacing

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