Histone demethylase LSD1 deficiency and biological sex: impact on blood pressure and aldosterone production

in Journal of Endocrinology
Correspondence should be addressed to L H Pojoga: lpojoga@partners.org

a(Y Huang, T M Yao, D Brooks, G K Adler, J R Romero, J S Williams, L H Pojoga and G H Williams are now at Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, USA)

b(P Y Ting is now at UCSI University, Kuala Terengganu Campus Bukit Khor, Mukim Rusila, Marang, Terengganu Darul Iman, Malaysia)

c(T Homma is now at Daiichi-Sankyo, Tokyo, Japan)

d(I K Rangel is now at Faculdade de Medicina da Universidade de São Paulo Av. Dr. Arnoldo, São Paulo – SP, Brazil)

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Human risk allele carriers of lysine-specific demethylase 1 (LSD1) and LSD1-deficient mice have salt-sensitive hypertension for unclear reasons. We hypothesized that LSD1 deficiency causes dysregulation of aldosterone’s response to salt intake resulting in increased cardiovascular risk factors (blood pressure and microalbumin). Furthermore, we determined the effect of biological sex on these potential abnormalities. To test our hypotheses, LSD1 male and female heterozygote-knockout (LSD1+/−) and WT mice were assigned to two age groups: 18 weeks and 36 weeks. Plasma aldosterone levels and aldosterone production from zona glomerulosa cells studied ex vivo were greater in both male and female LSD1+/− mice consuming a liberal salt diet as compared to WT mice consuming the same diet. However, salt-sensitive blood pressure elevation and increased microalbuminuria were only observed in male LSD1+/− mice. These data suggest that LSD1 interacts with aldosterone’s secretory response to salt intake. Lack of LSD1 causes inappropriate aldosterone production on a liberal salt diet; males appear to be more sensitive to this aldosterone increase as males, but not females, develop salt sensitivity of blood pressure and increased microalbuminuria. The mechanism responsible for the cardiovascular protective effect in females is uncertain but may be related to estrogen modulating the effect of mineralocorticoid receptor activation.

 

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Figures

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    RT-PCR of lysine-specific demethylase-1 (LSD1) mRNA expression in heart tissues from male (A) and female (B) mice. Data represent mean ± s.e.m. (n = 4). Statistical analyses were conducted using unpaired t-test (two-tailed). *P < 0.001 vs same-age WT.

  • View in gallery

    Systolic blood pressure (SBP) in male (A) and female (B) mice on a liberal salt diet. Data represent mean ± s.e.m. (sample sizes per genotype group: 18 week males: 20–21; 36 week males: 11–13; 18 week females: 21–27; 36 week females: 25–29). Statistical analyses were conducted using unpaired t-test (two-tailed). *P < 0.00001; #P < 0.05 vs same-age WT.

  • View in gallery

    Ex vivo aldosterone secretion and response to secretagogues (ANGII, 107M and K+, 8.7 mM) in adrenal ZG cells from male (A) and female (B) mice consuming a liberal salt diet. Data represent mean ± s.e.m. Sample size is 3–4/condition for males and 6–10/condition for females. *P < 0.05 vs corresponding measurements in WT.

  • View in gallery

    Plasma aldosterone and corticosterone levels in male (A and C) and female (B and D) mice consuming a liberal salt diet. Data represent mean ± s.e.m. Sample sizes for ALDO (corticosterone) per genotype group were: 18 week males: 9 (6); 36 week males: 17–19 (6); 18 week females: 9–10 (6); 36 week females: 12–14 (13–14). Statistical analyses were conducted using unpaired t-test (two-tailed), except for the data in panel A), where the Fisher’s exact test was used. *P < 0.05 vs same-age WT.

  • View in gallery

    Cardiac MR protein levels relative to β-tubulin in male (A) and female (B) mice. Data represent mean ± s.e.m. (n = 6/group). Statistical analyses were conducted using unpaired t-test (two-tailed) for (A) and Fisher’s exact test for (B). Gels for MR and β-tubulin immunoreactive bands are presented at the bottom of corresponding graphs. *P < 0.01 vs same-age WT.

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