期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 41, 期 1, 页码 269-283出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.120.314407
关键词
aneurysm; angiotensin; human; sex chromosome; Turner syndrome
资金
- American Heart Association [18SFRN3390001]
- National Institutes of Health [R01HL107326]
- Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine
The number of X chromosomes influences the development of aortopathies, with the absence of a second X chromosome promoting diffuse Ang II-induced aortopathies in females. This study demonstrates the role of sex chromosomes in disease development and highlights the importance of X chromosome genes in regulating aortic pathologies.
Objective: Turner syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of Ang II (angiotensin II)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of Ang II-induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XX female mice [XXF] or XO female mice [XOF]) on an C57BL/6J (ascending aortopathies) or low-density lipoprotein receptor deficient (Ldlr(-/-)) background (descending and abdominal aortopathies) compared with XY males (XYM). To induce aortopathies, mice were infused with Ang II. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than Ang II-infused XXF or XYM. Ang II-infused XOF (Ldlr(-/-)) exhibited similar incidences of thoracic (XOF, 50%; XYM, 71%) and abdominal aortopathies (XOF, 83%; XYM, 71%) as XYM, which were greater than XXF (XXF, 0%). Abdominal aortic lumen diameters and maximal external diameters were similar between XOF and XYM but greater than XXF, and these effects persisted with extended Ang II infusions. Larger aortic lumen diameters, abdominal aortopathy incidence (XXF, 20%; XOF, 75%), and maximal aneurysm diameters (XXF, 1.020.17; XOF, 1.96 +/- 0.32 mm; P=0.027) persisted in ovariectomized Ang II-infused XOF mice. Data from RNA-seq demonstrated that X chromosome genes that escape X-inactivation (histone lysine demethylases Kdm5c and Kdm6a) exhibited lower mRNA abundance in aortas of XOF than XXF (P=0.033 and 0.024, respectively). Conversely, DNA methylation was higher in aortas of XOF than XXF (P=0.038). Conclusions: The absence of a second X chromosome promotes diffuse Ang II-induced aortopathies in females.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据