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HDAC9基因可影响主动脉钙化
作者:小柯机器人 发布时间:2019/10/29 14:03:45

HDAC9基因与动脉粥样硬化性主动脉钙化有关,并影响血管平滑肌细胞表型,这一成果由美国麻省总医院Christopher J. O’Donnell和Rajeev Malhotra等研究人员近期取得。该研究于10月28日在线发表于《自然—遗传学》。

研究人员进行了全基因组关联荟萃分析,以确定与腹主动脉钙化程度(n=9417)或胸主动脉钙化程度(n=8422)相关的单核苷酸多态性(SNP)。在全基因组水平上,两个遗传位点HDAC9和RAP1GAP与腹主动脉钙化相关(P <5.0×10-8)。在全基因组阈值时,没有SNP与胸主动脉钙化相关。HDAC9在人类主动脉平滑肌细胞中表达的增加促进了钙化以及收缩力的降低,而HDAC9在人类主动脉平滑肌细胞中的抑制作用则抑制钙化并增强细胞收缩力。在基质Gla蛋白缺乏小鼠中(人类血管钙化模型),缺乏HDAC9的小鼠主动脉钙化减少了40%,并提高了存活率。

这项转化基因组研究确定了与腹主动脉钙化相关的第一个遗传风险位点,并描述了HDAC9在血管钙化发展中的未知作用。

据介绍,主动脉钙化是将来心血管事件的重要独立预测因子。

附:英文原文

Title: HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype

Author: Rajeev Malhotra, Andreas C. Mauer, Christian L. Lino Cardenas, Xiuqing Guo, Jie Yao, Xiaoling Zhang, Florian Wunderer, Albert V. Smith, Quenna Wong, Sonali Pechlivanis, Shih-Jen Hwang, Judy Wang, Lingyi Lu, Christopher J. Nicholson, Georgia Shelton, Mary D. Buswell, Hanna J. Barnes, Haakon H. Sigurslid, Charles Slocum, Caitlin O Rourke, David K. Rhee, Aranya Bagchi, Sagar U. Nigwekar, Emmanuel S. Buys, Catherine Y. Campbell, Tamara Harris, Matthew Budoff, Michael H. Criqui, Jerome I. Rotter, Andrew D. Johnson, Ci Song, Nora Franceschini, Stephanie Debette, Udo Hoffmann, Hagen Klsch, Markus M. Nthen, Sigurdur Sigurdsson, Barry I. Freedman, Donald W. Bowden, Karl-Heinz Jckel, Susanne Moebus, Raimund Erbel, Mary F. Feitosa, Vilmundur Gudnason, George Thanassoulis, Warren M. Zapol, Mark E. Lindsay, Donald B. Bloch, Wendy S. Post, Christopher J. ODonnell

Issue&Volume: 2019-10-28

Abstract: Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n=9,417) or descending thoracic aortic calcification (n=8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P5.0×108). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

DOI: 10.1038/s41588-019-0514-8

Source: https://www.nature.com/articles/s41588-019-0514-8

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex