Krug Alexander W, Tille Eric, Sun Bei, Pojoga Luminita, Williams Jonathan, Chamarthi Bindu, Lichtman Andrew H, Hopkins Paul N, Adler Gail K, Williams Gordon H
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA,
Age (Dordr). 2013 Oct;35(5):1809-20. doi: 10.1007/s11357-012-9480-0. Epub 2012 Oct 2.
How interactions of an individual's genetic background and environmental factors, such as dietary salt intake, result in age-associated blood pressure elevation is largely unknown. Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation and modification of gene transcription. We have shown previously that hypertensive African-American minor allele carriers of the LSD1 single nucleotide polymorphism (rs587168) display blood pressure salt sensitivity. Our goal was to further examine the effects of LSD1 genotype variants on interactions between dietary salt intake, age, and blood pressure. We found that LSD1 single nucleotide polymorphism (rs7548692) predisposes to increasing salt sensitivity during aging in normotensive Caucasian subjects. Using a LSD1 heterozygous knockout mouse model, we compared blood pressure values on low (0.02 % Na(+)) vs. high (1.6 % Na(+)) salt intake. Our results demonstrate significantly increased blood pressure salt sensitivity in LSD1-deficient compared to wild-type animals with age, confirming our findings of salt sensitivity in humans. Elevated blood pressure in LSD1(+/-) mice is associated with total plasma volume expansion and altered renal Na(+) excretion. In summary, our human and animal studies demonstrate that LSD1 is a genetic factor that interacts with dietary salt intake modifying age-associated blood pressure increases and salt sensitivity through alteration of renal Na(+) handling.
个体的遗传背景与环境因素（如饮食中的盐摄入量）之间的相互作用如何导致与年龄相关的血压升高，目前很大程度上尚不清楚。赖氨酸特异性去甲基化酶-1（LSD1）是一种组蛋白去甲基化酶，介导基因转录的表观遗传调控和修饰。我们之前已经表明，LSD1单核苷酸多态性（rs587168）的高血压非裔美国次要等位基因携带者表现出血压盐敏感性。我们的目标是进一步研究LSD1基因变异对饮食盐摄入量、年龄和血压之间相互作用的影响。我们发现，LSD1单核苷酸多态性（rs7548692）使正常血压的白种人在衰老过程中盐敏感性增加。使用LSD1杂合敲除小鼠模型，我们比较了低（0.02% Na(+)）与高（1.6% Na(+)）盐摄入量时的血压值。我们的结果表明，与野生型动物相比，随着年龄增长，LSD1缺陷型动物的血压盐敏感性显著增加，证实了我们在人类中发现的盐敏感性。LSD1(+/-)小鼠血压升高与血浆总量扩张和肾钠排泄改变有关。总之，我们的人体和动物研究表明，LSD1是一种遗传因素，它通过改变肾脏对钠的处理，与饮食盐摄入量相互作用，改变与年龄相关的血压升高和盐敏感性。
