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Dysfunctional nitric oxide signalling increases risk of myocardial infarction
文献类型：期刊论文
| 作者 | Erdmann, Jeanette1,2; Stark, Klaus3,4; Esslinger, Ulrike B.3,5; Rumpf, Philipp Moritz6,7,8; Koesling, Doris9; de Wit, Cor2,10; Kaiser, Frank J.2,11; Braunholz, Diana11; Medack, Anja1; Fischer, Marcus3 |
| 刊名 | NATURE
 |
| 出版日期 | 2013 |
| 卷号 | 504期号:7480 |
| ISSN号 | 1478-6419 |
| 通讯作者 | Hengstenberg, C (reprint author), Deutsch Herzzentrum Munich, D-80636 Munich, Germany. |
| 产权排序 | 35 |
| 英文摘要 | Myocardial infarction, a leading cause of death intheWesternworld(1), usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery(2). The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history(3). Nextgeneration sequencing in families with several affected individuals has revolutionized mutation identification(4). Here we report the segregation of two private, heterozygous mutations in two functionally relatedgenes, GUCY1A3 (p.Leu163Phefs*24) andCCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha 1 subunit of soluble guanylyl cyclase (alpha 1-sGC)(5), and CCT7 encodes CCT eta, a member of the tailless complex polypeptide 1 ring complex(6), which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation(7). Wedemonstratein vitro that mutations inbothGUCY1A3 and CCT7 severely reduce alpha 1-sGC as well as beta 1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxideinduced cGMP formation. Mice deficient in alpha 1-sGC protein displayed accelerated thrombus formation in themicrocirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction. |
| 学科主题 | Medical psychology |
| WOS标题词 | Science & Technology |
| 类目[WOS] | Multidisciplinary Sciences |
| 研究领域[WOS] | Science & Technology - Other Topics |
| 关键词[WOS] | CORONARY-ARTERY-DISEASE ; SOLUBLE GUANYLATE-CYCLASE ; GENOME-WIDE ASSOCIATION ; SUSCEPTIBILITY LOCI ; ADULTS |
| 收录类别 | SCI |
| 项目简介 | We thank all the family members who participated in this research. Without the continuous support of these patients over more than 15 years, the present work would not have been possible. We would like to thank S. Wrobel, S. Stark, A. Liebers, K. Franke, J. Stegmann-Frehse, M. Behrensen, M. Schmid, J. Eckhold, D. Wollner, U. Krabbe and J. Simon for technical assistance. Furthermore, we would like to thank M. Becker, N. Buchholz, I. Demuth, R. Eckardt, H. Heekeren, U. Lindenberger, M. Lovden, L. Muller, W. Nietfeld, G. Pawelec, F. Schmiedeck, T. Siedler and G. G. Wagner for their contributions to BASE-II. We also would like to thank S. Herterich and S. Gambaryan for advice, and B. Mayer, U. Hubauer, K.-H. Ameln and A. Grosshennig for help with GerMIFS. We thank WTCCC+ and the WTCCC-CAD2 investigators for access to their data. The study is supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 (01GS0417) and NGFN-plus (01GS0832)), the FP6 and FP7 EU-funded integrated projects Cardiogenics (LSHM-CT-2006-037593), ENGAGE (201413), and GEUVADIS (261123), the binational BMBF/ANR funded project CARDomics (01KU0908A), the local focus programs 'Kardiovaskulare Genomforschung' and 'Medizinische Genetik' of the Universitat zu Lubeck, and the University Hospital of Regensburg, Germany. The German Federal Ministry for Education and Research provided funding for BASE-II (BMBF; grant no. 16SV5538). Support by NSFC grant 30730057 from the Chinese Government (to J.O.) is gratefully acknowledged. N. J. S. holds a Chair funded by the British Heart Foundation, and is supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. U. W. is supported by the BMBF(01EO1003). M. M. N. is a member of the DFG-funded Excellence Cluster ImmunoSensation. |
| 原文出处 | http://www.nature.com/nature/journal/v504/n7480/pdf/nature12722.pdf |
| 语种 | 英语 |
| WOS记录号 | WOS:000328575300051 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/10825]  |
| 专题 | 心理研究所_健康与遗传心理学研究室 |
| 作者单位 | 1.Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany 2.German Ctr Cardiovasc Res DZHK, D-23562 Lubeck, Germany 3.Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany 4.Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany 5.INSERM, UMR S937, Paris, France 6.Deutsch Herzzentrum Munich, D-80636 Munich, Germany 7.Tech Univ Munich, Klinikum Rechts Isar, Med Klin 1, D-80636 Munich, Germany 8.German Ctr Cardiovasc Res DZHK, D-80636 Munich, Germany 9.Ruhr Univ Bochum, Dept Pharmacol & Toxicol, D-44801 Bochum, Germany 10.Med Univ Lubeck, Inst Physiol, D-23562 Lubeck, Germany |
| 推荐引用方式 GB/T 7714 | Erdmann, Jeanette,Stark, Klaus,Esslinger, Ulrike B.,et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction[J]. NATURE,2013,504(7480). |
| APA | Erdmann, Jeanette.,Stark, Klaus.,Esslinger, Ulrike B..,Rumpf, Philipp Moritz.,Koesling, Doris.,...&CARDIoGRAM.(2013).Dysfunctional nitric oxide signalling increases risk of myocardial infarction.NATURE,504(7480). |
| MLA | Erdmann, Jeanette,et al."Dysfunctional nitric oxide signalling increases risk of myocardial infarction".NATURE 504.7480(2013). |
入库方式： OAI收割
来源：心理研究所
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