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Fulltext Lysine-Specific Demethylase-1 Deficiency Increases Agonist Signaling Via the Mineralocorticoid Receptor

Treesaranuwattana T, Wong KYH, Brooks DL, Tay CS, Williams GH, Williams JS, et al.

Hypertension, 2020 04;75(4):1045-1053.
PMID: 32160100 DOI: 10.1161/HYPERTENSIONAHA.119.13821

LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency (LSD1+/-) in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in LSD1+/- mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency-mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in LSD1+/- mouse kidney tissues, aldosterone secretion from LSD1+/- glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.
Fulltext Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants

Tan JW, Gupta T, Manosroi W, Yao TM, Hopkins PN, Williams JS, et al.

JCI Insight, 2017 12 07;2(23).
PMID: 29212952 DOI: 10.1172/jci.insight.95992

Compared with persons of European descent (ED), persons of African descent (AD) have lower aldosterone (ALDO) levels, with the assumption being that the increased cardiovascular disease (CVD) risk associated with AD is not related to ALDO. However, the appropriateness of the ALDO levels for the volume status in AD is unclear. We hypothesized that, even though ALDO levels are lower in AD, they are inappropriately increased, and therefore, ALDO could mediate the increased CVD in AD. To test this hypothesis, we analyzed data from HyperPATH - 1,788 individuals from the total cohort and 765 restricted to ED-to-AD in a 2:1 match and genotyped for the endothelin-1 gene (EDN1). Linear regression analyses with adjustments were performed. In the total and restricted cohorts, PRA, ALDO, and urinary potassium levels were significantly lower in AD. However, in the AD group, greater ALDO dysregulation was present as evidenced by higher ALDO/plasma renin activity (PRA) ratios (ARR) and sodium-modulated ALDO suppression-to-stimulation indices. Furthermore, EDN1 minor allele carriers had significantly greater ARRs than noncarriers but only in the AD group. ARR levels were modulated by a significant interaction between EDN1 and AD. Thus, EDN1 variants may identify particularly susceptible ADs who will be responsive to treatment targeting ALDO-dependent pathways (e.g., mineralocorticoid-receptor antagonists).
Fulltext Lysine-specific demethylase 1 deficiency modifies aldosterone synthesis in a sex-specific manner

Tan YJD, Brooks DL, Wong KYH, Huang Y, Romero JR, Williams JS, et al.

J Endocrinol, 2023 Jan 01;256(1).
PMID: 36327153 DOI: 10.1530/JOE-22-0141

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

Huang Y, Ting PY, Yao TM, Homma T, Brooks D, Katayama Rangel IA, et al.

J Endocrinol, 2018 Nov 01.
PMID: 30400034 DOI: 10.1530/JOE-18-0247

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 wild type (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.
Fulltext Striatin Gene Polymorphic Variants Are Associated With Salt Sensitive Blood Pressure in Normotensives and Hypertensives

Gupta T, Connors M, Tan JW, Manosroi W, Ahmed N, Ting PY, et al.

Am J Hypertens, 2017 Dec 08;31(1):124-131.
PMID: 28985281 DOI: 10.1093/ajh/hpx146

BACKGROUND: Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms.
METHODS: We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/-).
RESULTS: The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN-SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/- mice. No significant associations were observed with other volume regulated systems.
CONCLUSIONS: These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention.
Fulltext Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway

Haas AV, En Yee L, Yuan YE, Wong YH, Hopkins PN, Jeunemaitre X, et al.

Hypertension, 2021 Dec;78(6):1809-1817.
PMID: 34757767 DOI: 10.1161/HYPERTENSIONAHA.121.18033

[Figure: see text].
Fulltext The Association of Estrogen Receptor-β Gene Variation With Salt-Sensitive Blood Pressure

Manosroi W, Tan JW, Rariy CM, Sun B, Goodarzi MO, Saxena AR, et al.

J Clin Endocrinol Metab, 2017 11 01;102(11):4124-4135.
PMID: 28938457 DOI: 10.1210/jc.2017-00957

Context: Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-β, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle.
Objective: To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women.
Methods: Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging.
Results: Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1.
Conclusions: The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.