Lysine-specific demethylase 1 deficiency modifies aldosterone synthesis in a sex-specific manner.
Lysine-specific demethylase 1 deficiency modifies aldosterone synthesis in a sex-specific manner.
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DOI：
10.1530/joe-22-0141
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发表时间：
2023-01-01
影响因子：
4
通讯作者：
Pojoga, Luminita H.
中科院分区：
文献类型：
--
作者：
Tan, Yi Jun Desmond;Brooks, Danielle L.;Wong, Kelly Yin Han;Huang, Yuefei;Romero, Jose R.;Williams, Jonathan S.;Pojoga, Luminita H.
生物性别会影响心血管疾病的发展并改变醛固酮 (ALDO) 和血压 (BP) 表型：女性会分泌更多的 ALDO，并且她们的肾上腺肾小球细胞对刺激更敏感。非洲人的赖氨酸特异性去甲基酶 1 (LSD1) 变异和小鼠的 LSD1 缺乏与 BP 和/或 ALDO 表型相关。这项研究在 18 周和 40 周龄的野生型 (WT) 和 LSD1+/- 小鼠中进行，旨在确定：1) 性别是否会改变 ALDO 生物合成酶； 2）LSD1缺乏会破坏性别对这些酶的影响； 3) 在每个基因型内，ALDO生物合成（邻近表型）、血浆ALDO（中间表型）和BP水平（远端表型）之间存在正相关关系； 4) 性别和 LSD1 基因型对这些表型相互作用。在 WT 小鼠中，雌性会增加 ALDO 生物合成中早期酶的表达，但不会增加 ALDO 水平或 SBP。然而，与男性相比，LSD1+/- 雌性中的酶表达向下移动，因此早期酶水平相似，但晚期酶水平明显较低。在两个年龄组中，LSD1 缺乏都会改变肾上腺酶的表达，从而以性别特异性的方式改变循环 ALDO 水平和 SBP。最后，显着的性别/LSD1 基因型相互作用调节小鼠的三种表型。总之，小鼠的生物性别与 LSD1 缺陷相互作用，从而改变了几种表型：1）近端（ALDO 生物合成酶）； 2）中间体（循环ALDO）； 3) 远距离（SBP）。这些结果为更好地理解生物性别和 LSD1 在以下方面的作用提供了切入点：1) 高血压异质性；2) 提供更个性化的治疗。
Biologic sex influences the development of cardiovascular disease and modifies aldosterone (ALDO) and blood pressure (BP) phenotypes: females secrete more ALDO, and their adrenal glomerulosa cell is more sensitive to stimulation. Lysine-specific demethylase 1 (LSD1) variants in Africans and LSD1 deficiency in mice associate with BP and/or ALDO phenotypes. This study, in 18- and 40-week-old wild type (WT) and LSD1+/− mice, was designed to determine whether: 1) sex modifies ALDO biosynthetic enzymes; 2) LSD1 deficiency disrupts the effect of sex on these enzymes; 3) within each genotype, there is a positive relationship between ALDO biosynthesis (proximate phenotype), plasma ALDO (intermediate phenotype) and BP levels (distant phenotype); and 4) sex and LSD1 genotype interact on these phenotypes. In WT mice, female sex increases the expression of early enzymes in ALDO biosynthesis, but not ALDO levels or SBP. However, enzyme expressions are shifted downward in LSD1+/− females vs. males, so that early enzyme levels are similar but the late enzymes are substantially lower. In both age groups, LSD1 deficiency modifies the adrenal enzyme expressions, circulating ALDO levels and SBP in a sex specific manner. Finally, significant sex/LSD1 genotype interactions modulate the three phenotypes in mice. In conclusion, biologic sex in mice interacts with LSD1 deficiency to modify several phenotypes: 1) proximal (ALDO biosynthetic enzymes); 2) intermediate (circulating ALDO); and 3) distant (SBP). These results provide entrée to better understand the roles of biologic sex and LSD1 in: 1) hypertension heterogeneity and 2) in providing more personalized treatment.
影响因子：
2.5
作者：
Wasinski F;Teixeira PDS;List EO;Kopchick JJ;Donato J Jr
通讯作者：
Donato J Jr