Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, Houston, TX, 77030, USA.
Department of Integrative Biology and Physiology, UCLA, 610 Charles Young Drive South, Los Angeles, CA, 90095, USA.
Transl Stroke Res. 2023 Oct;14(5):776-789. doi: 10.1007/s12975-022-01070-z. Epub 2022 Jul 29.
Post-menopausal women become vulnerable to stroke and have poorer outcomes and higher mortality than age-matched men, and previous studies suggested that sex chromosomes play a vital role in mediating stroke sensitivity in the aged. It is unknown if this is due to effects of the X or Y chromosome. The present study used the XY* mouse model (with four genotypes: XX and XO gonadal females and XY and XXY gonadal males) to compare the effect of the X vs. Y chromosome compliment in stroke. Aged (18-20 months) and gonadectomized young (8-12 weeks) mice were subjected to a 60-min middle cerebral artery occlusion. Infarct volume and behavioral deficits were quantified 3 days after stroke. Microglial activation and infiltration of peripheral leukocytes in the aged ischemic brain were assessed by flow cytometry. Plasma inflammatory cytokine levels by ELISA, and brain expression of two X chromosome-linked genes, KDM6A and KDM5C by immunochemistry, were also examined. Both aged and young XX and XXY mice had worse stroke outcomes compared to XO and XY mice, respectively; however, the difference between XX vs. XXY and XO vs. XY aged mice was minimal. Mice with two copies of the X chromosome showed more robust microglial activation, higher brain-infiltrating leukocytes, elevated plasma cytokine levels, and enhanced co-localization of KDM6A and KDM5C with Iba1 cells after stroke than mice with one X chromosome. The number of X chromosomes mediates stroke sensitivity in aged mice, which might be processed through the X chromosome-linked genes and the inflammatory responses.
绝经后女性比同龄男性更容易中风，且预后更差、死亡率更高，先前的研究表明性染色体在调节老年中风易感性方面起着至关重要的作用。目前尚不清楚这是由于 X 染色体还是 Y 染色体的作用。本研究使用 XY* 小鼠模型（具有四种基因型：XX 和 XO 性腺雌性和 XY 和 XXY 性腺雄性）来比较 X 染色体与 Y 染色体在中风中的作用。老年（18-20 个月）和去势年轻（8-12 周）小鼠接受 60 分钟大脑中动脉闭塞。中风后 3 天定量测定梗死体积和行为缺陷。通过流式细胞术评估老年缺血性大脑中微胶质细胞的激活和外周白细胞的浸润。通过 ELISA 测定血浆炎症细胞因子水平，通过免疫组织化学测定两个 X 染色体连锁基因 KDM6A 和 KDM5C 在大脑中的表达。与 XO 和 XY 小鼠相比，老年和年轻的 XX 和 XXY 小鼠的中风结局均较差；然而，XX 与 XXY 以及 XO 与 XY 老年小鼠之间的差异很小。具有两条 X 染色体的小鼠在中风后表现出更强烈的小胶质细胞激活、更高的大脑浸润白细胞、更高的血浆细胞因子水平以及 KDM6A 和 KDM5C 与 Iba1 细胞的共定位增强，而具有一条 X 染色体的小鼠则不然。X 染色体的数量调节老年小鼠的中风敏感性，这可能是通过 X 染色体连锁基因和炎症反应来实现的。
