Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Faculty of Medicine & Health Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia.
J Endocrinol. 2022 Dec 12;256(1). doi: 10.1530/JOE-22-0141. Print 2023 Jan 1.
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 are associated 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 systolic blood pressure (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 entry to better understand the roles of biological sex and LSD1 in (1) hypertension heterogeneity and (2) providing more personalized treatment.
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：女性分泌更多的 ALDO，其肾上腺球状带细胞对刺激更敏感。非洲人的赖氨酸特异性去甲基酶 1（LSD1）变体和小鼠中的 LSD1 缺乏与 BP 和/或 ALDO 表型有关。本研究旨在 18 周和 40 周龄的野生型（WT）和 LSD1+/- 小鼠中确定以下内容：（1）性别是否改变 ALDO 生物合成酶；（2）LSD1 缺乏是否破坏性别对这些酶的影响；（3）在每种基因型中，ALDO 生物合成（近似表型）、血浆 ALDO（中间表型）和 BP 水平（远距表型）之间存在正相关；（4）性别和 LSD1 基因型对这些表型是否存在相互作用。在 WT 小鼠中，雌性增加了 ALDO 生物合成的早期酶的表达，但不增加 ALDO 水平或收缩压（SBP）。然而，LSD1+/- 雌性的酶表达向下移动，使得早期酶水平相似，但晚期酶水平显著降低。在两个年龄组中，LSD1 缺乏以性别特异性的方式改变了肾上腺酶表达、循环 ALDO 水平和 SBP。最后，显著的性别/LSD1 基因型相互作用调节了小鼠的三种表型。总之，小鼠的生物性别与 LSD1 缺乏相互作用，可改变多种表型：（1）近距（ALDO 生物合成酶）；（2）中间（循环 ALDO）；（3）远距（SBP）。这些结果为更好地理解生物性别和 LSD1 在（1）高血压异质性和（2）提供更个性化治疗中的作用提供了依据。
