Lysine-specific demethylase 1 deficiency modifies aldosterone synthesis in a sex-specific manner

in Journal of Endocrinology
Authors:
Yi Jun Desmond Tan 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

Search for other papers by Yi Jun Desmond Tan in
Current site
Google Scholar
PubMed Close
,
Danielle L Brooks Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Search for other papers by Danielle L Brooks in
Current site
Google Scholar
PubMed Close
,
Kelly Yin Han Wong 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

Search for other papers by Kelly Yin Han Wong in
Current site
Google Scholar
PubMed Close
,
Yuefei Huang Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Search for other papers by Yuefei Huang in
Current site
Google Scholar
PubMed Close
,
Jose R Romero Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Search for other papers by Jose R Romero in
Current site
Google Scholar
PubMed Close
,
Jonathan S Williams Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Search for other papers by Jonathan S Williams in
Current site
Google Scholar
PubMed Close
, and
Luminita H Pojoga Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Search for other papers by Luminita H Pojoga in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-9448-6333

Correspondence should be addressed to L H Pojoga: lpojoga@partners.org

*(Y J Desmond Tan and D L Brooks contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-22-0141
Volume/Issue:
Volume 256: Issue 1
Article Type:
Research Article
Article ID:
e220141
Online Publication Date:
12 Dec 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
Rent on DeepDyve

Sign up for journal news

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.

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 731 110 1
PDF Downloads 190 14 1

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2022
Article ID:
e220141
Article Type:
Research Article
Received Date:
07 Oct 2022
Accepted Date:
03 Nov 2022
Print Publication Date:
01 Jan 2023
Online Publication Date:
12 Dec 2022
Keywords:
lysine-specific demethylase 1; aldosterone biosynthesis; sex; blood pressure; cortical adrenal enzymes

  • Barrett Mueller K, Lu Q, Mohammad NN, Luu V, McCurley A, Williams GH, Adler GK, Karas RH & Jaffe IZ 2014 Estrogen receptor inhibits mineralocorticoid receptor transcriptional regulatory function. Endocrinology 155 4461–4472. (https://doi.org/10.1210/en.2014-1270)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Baudrand R, Pojoga LH, Romero Jr & Williams GH 2014 Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin. Current Opinion in Nephrology and Hypertension 23 32–37. (https://doi.org/10.1097/01.mnh.0000436543.48391.e0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Benedetti R, Dell'Aversana C, De Marchi T, Rotili D, Liu NQ, Novakovic B, Boccella S, Di Maro S, Cosconati S & Baldi A et al.2019 Inhibition of histone demethylases LSD1 and UTX regulates ERalpha signaling in breast cancer. Cancers (Basel) 11 2027. (https://doi.org/10.3390/cancers11122027)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bennesch MA, Segala G, Wider D & Picard D 2016 LSD1 engages a corepressor complex for the activation of the estrogen receptor alpha by estrogen and cAMP. Nucleic Acids Research 44 8655–8670. (https://doi.org/10.1093/nar/gkw522)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Brooks DL, Garza AE, Caliskan Guzelce E, Gholami SK, Treesaranuwattana T, Maris S, Ranjit S, Tay CS, Lee JM & Romero Jr et al.2020 mTORC1 deficiency modifies volume homeostatic responses to dietary sodium in a sex-specific manner. Endocrinology 161. (https://doi.org/10.1210/endocr/bqaa041)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH & Vaidya A 2020 The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Annals of Internal Medicine 173 10–20. (https://doi.org/10.7326/M20-0065)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Caroccia B, Seccia TM, Barton M & Rossi GP 2016 Estrogen signaling in the adrenal cortex: implications for blood pressure sex differences. Hypertension 68 840–848. (https://doi.org/10.1161/HYPERTENSIONAHA.116.07660)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Carvalho JJ, Baruzzi RG, Howard PF, Poulter N, Alpers MP, Franco LJ, Marcopito LF, Spooner VJ, Dyer AR & Elliott P 1989 Blood pressure in four remote populations in the INTERSALT Study. Hypertension 14 238–246. (https://doi.org/10.1161/01.hyp.14.3.238)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen C, Wang Y, Wang S, Liu Y, Zhang J, Xu Y, Zhang Z, Bao W & Wu S 2017 LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1. International Journal of Oncology 50 942–952. (https://doi.org/10.3892/ijo.2017.3849)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chong C, Hamid A, Yao T, Garza AE, Pojoga LH, Adler GK, Romero Jr & Williams GH 2017 Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling. Journal of Endocrinology 232 525–534. (https://doi.org/10.1530/JOE-16-0452)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Danser AH, Derkx FH, Schalekamp MA, Hense HW, Riegger GA & Schunkert H 1998 Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. Journal of Hypertension 16 853–862. (https://doi.org/10.1097/00004872-199816060-00017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Daugherty SL, Masoudi FA, Ellis JL, Ho PM, Schmittdiel JA, Tavel HM, Selby JV, O'Connor PJ, Margolis KL & Magid DJ 2011 Age-dependent gender differences in hypertension management. Journal of Hypertension 29 1005–1011. (https://doi.org/10.1097/HJH.0b013e3283449512)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Doumas M, Papademetriou V, Faselis C & Kokkinos P 2013 Gender differences in hypertension: myths and reality. Current Hypertension Reports 15 321–330. (https://doi.org/10.1007/s11906-013-0359-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Epstein M 2001 Aldosterone as a determinant of cardiovascular and renal dysfunction. Journal of the Royal Society of Medicine 94 378–383. (https://doi.org/10.1177/014107680109400803)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Faulkner JL & Belin de Chantemele EJ 2020 Female sex, a major risk factor for salt-sensitive hypertension. Current Hypertension Reports 22 99. (https://doi.org/10.1007/s11906-020-01113-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gholami SK, Tay CS, Lee JM, Zagoren E, Maris SA, Wong JY, Garza AE, Caliskan Guzelce E, Pojoga LH & Adler GK et al.2021 Biological sex modifies aldosterone's secretion at a cellular level. Journal of Endocrinology 252 1–13. (https://doi.org/10.1530/JOE-21-0126)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ha SK 2014 Dietary salt intake and hypertension. Electrolyte and Blood Pressure 12 7–18. (https://doi.org/10.5049/EBP.2014.12.1.7)

  • Hirshoren N, Tzoran I, Makrienko I, Edoute Y, Plawner MM, Itskovitz-Eldor J & Jacob G 2002 Menstrual cycle effects on the neurohumoral and autonomic nervous systems regulating the cardiovascular system. Journal of Clinical Endocrinology and Metabolism 87 1569–1575. (https://doi.org/10.1210/jcem.87.4.8406)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hollenberg NK, Williams GH, Burger B, Chenitz W, Hoosmand I & Adams DF 1976 Renal blood flow and its response to angiotensin II. An interaction between oral contraceptive agents, sodium intake, and the renin-angiotensin system in healthy young women. Circulation Research 38 35–40. (https://doi.org/10.1161/01.res.38.1.35)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Homma T, Homma M, Huang Y, Mayurasakorn K, Rodi NM, Hamid AAA, Hurwitz S, Yao T, Adler GK & Pojoga LH et al.2017 Combined salt and caloric restrictions: potential adverse outcomes. Journal of the American Heart Association 6 e005374. (https://doi.org/10.1161/JAHA.116.005374)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hosseini A & Minucci S 2017 A comprehensive review of lysine-specific demethylase 1 and its roles in cancer. Epigenomics 9 1123–1142. (https://doi.org/10.2217/epi-2017-0022)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huang Y, Ting PY, Yao TM, Homma T, Brooks D, Katayama Rangel I, Adler GK, Romero Jr, Williams JS & Pojoga LH et al.2019 Histone demethylase LSD1 deficiency and biological sex: impact on blood pressure and aldosterone production. Journal of Endocrinology 240 111–122. (https://doi.org/10.1530/JOE-18-0247)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Krug AW, Tille E, Sun B, Pojoga L, Williams J, Chamarthi B, Lichtman AH, Hopkins PN, Adler GK & Williams GH 2013 Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake. Age 35 1809–1820. (https://doi.org/10.1007/s11357-012-9480-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee K, Kitagawa M, Liao PJ, Virshup DM & Lee SH 2020 A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression. Oncogenesis 9 2. (https://doi.org/10.1038/s41389-019-0185-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Majello B, Gorini F, Sacca CD & Amente S 2019 Expanding the role of the histone lysine-specific demethylase LSD1 in cancer. Cancers (Basel) 11 324. (https://doi.org/10.3390/cancers11030324)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Malendowicz LK 1980 Sex differences in adrenocortical structure and function. VI. Long-term effect of gonadectomy and testosterone or estradiol replacement on rat adrenal cortex. Endokrinologie 75 311–323.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Manosroi W & Williams GH 2019 Genetics of human primary hypertension: focus on hormonal mechanisms. Endocrine Reviews 40 825–856. (https://doi.org/10.1210/er.2018-00071)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R & Schule R 2005 LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437 436–439. (https://doi.org/10.1038/nature04020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Miller JA, Anacta LA & Cattran DC 1999 Impact of gender on the renal response to angiotensin II. Kidney International 55 278–285. (https://doi.org/10.1046/j.1523-1755.1999.00260.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Miller WL 2018 Mechanisms in endocrinology: rare defects in adrenal steroidogenesis. European Journal of Endocrinology 179 R125–R141. (https://doi.org/10.1530/EJE-18-0279)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Muller J & Lauber M 1991 Regulation of aldosterone biosynthesis: a continual challenge. American Journal of Hypertension 4 280–282. (https://doi.org/10.1093/ajh/4.3.280)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • O'Donnell E, Floras JS & Harvey PJ 2014 Estrogen status and the renin angiotensin aldosterone system. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 307 R498–R500. (https://doi.org/10.1152/ajpregu.00182.2014)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ostchega Y, Yoon SS, Hughes J & Louis T 2008 Hypertension awareness, treatment, and control--continued disparities in adults: United States, 2005–2006. NCHS Data Brief 3 1–8.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pazoki R, Dehghan A, Evangelou E, Warren H, Gao H, Caulfield M, Elliott P & Tzoulaki I 2018 Genetic predisposition to high blood pressure and lifestyle factors: associations with midlife blood pressure levels and cardiovascular events. Circulation 137 653–661. (https://doi.org/10.1161/CIRCULATIONAHA.117.030898)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pojoga LH, Romero Jr, Yao TM, Loutraris P, Ricchiuti V, Coutinho P, Guo C, Lapointe N, Stone Jr & Adler GK et al.2010 Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II. Endocrinology 151 1236–1246. (https://doi.org/10.1210/en.2009-0514)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pojoga LH, Williams JS, Yao TM, Kumar A, Raffetto JD, do Nascimento GR, Reslan OM, Adler GK, Williams GH & Shi Y et al.2011 Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. American Journal of Physiology. Heart and Circulatory Physiology 301 H1862–H1871. (https://doi.org/10.1152/ajpheart.00513.2011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Quinkler M, Meyer B, Bumke-Vogt C, Grossmann C, Gruber U, Oelkers W, Diederich S & Bahr V 2002 Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor. European Journal of Endocrinology 146 789–799. (https://doi.org/10.1530/eje.0.1460789)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ranjit S, Wong JY, Tan JW, Sin Tay C, Lee JM, Yin Han Wong K, Pojoga LH, Brooks DL, Garza AE & Maris SA et al.2019 Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses. JCI Insight 4 e129615. (https://doi.org/10.1172/jci.insight.129615)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roviezzo F, Cuzzocrea S, Di Lorenzo A, Brancaleone V, Mazzon E, Di Paola R, Bucci M & Cirino G 2007 Protective role of PI3-kinase-Akt-eNOS signalling pathway in intestinal injury associated with splanchnic artery occlusion shock. British Journal of Pharmacology 151 377–383. (https://doi.org/10.1038/sj.bjp.0707233)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shi Y, Lan F, Matson C, Mulligan P, Whetstine Jr, Cole PA, Casero RA & Shi Y 2004 Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119 941–953. (https://doi.org/10.1016/j.cell.2004.12.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shukri MZ, Tan JW, Manosroi W, Pojoga LH, Rivera A, Williams JS, Seely EW, Adler GK, Jaffe IZ & Karas RH et al.2018 Biological sex modulates the adrenal and blood pressure responses to angiotensin II. Hypertension 71 1083–1090. (https://doi.org/10.1161/HYPERTENSIONAHA.117.11087)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stazi G, Zwergel C, Valente S & Mai A 2016 LSD1 inhibitors: a patent review (2010–2015). Expert Opinion on Therapeutic Patents 26 565–580. (https://doi.org/10.1517/13543776.2016.1165209)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Szmuilowicz ED, Adler GK, Williams JS, Green DE, Yao TM, Hopkins PN & Seely EW 2006 Relationship between aldosterone and progesterone in the human menstrual cycle. Journal of Clinical Endocrinology and Metabolism 91 3981–3987. (https://doi.org/10.1210/jc.2006-1154)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Treesaranuwattana T, Wong KYH, Brooks DL, Tay CS, Williams GH, Williams JS & Pojoga LH 2020 Lysine-specific demethylase-1 deficiency increases agonist signaling via the mineralocorticoid receptor. Hypertension 75 1045–1053. (https://doi.org/10.1161/HYPERTENSIONAHA.119.13821)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Trejter M, Jopek K, Celichowski P, Tyczewska M, Malendowicz LK & Rucinski M 2015 Expression of estrogen, estrogen related and androgen receptors in adrenal cortex of intact adult male and female rats. Folia Histochemica et Cytobiologica 53 133–144. (https://doi.org/10.5603/FHC.a2015.0012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X & Shi L et al.2009 LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138 660–672. (https://doi.org/10.1016/j.cell.2009.05.050)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Williams GH 2005 Aldosterone biosynthesis, regulation, and classical mechanism of action. Heart Failure Reviews 10 7–13. (https://doi.org/10.1007/s10741-005-2343-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Williams JS, Chamarthi B, Goodarzi MO, Pojoga LH, Sun B, Garza AE, Raby BA, Adler GK, Hopkins PN & Brown NJ et al.2012 Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension. American Journal of Hypertension 25 812–817. (https://doi.org/10.1038/ajh.2012.43)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xing Y, Cohen A, Rothblat G, Sankaranarayanan S, Weibel G, Royer L, Francone OL & Rainey WE 2011 Aldosterone production in human adrenocortical cells is stimulated by high-density lipoprotein 2 (HDL2) through increased expression of aldosterone synthase (CYP11B2). Endocrinology 152 751–763. (https://doi.org/10.1210/en.2010-1049)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xue B, Johnson AK & Hay M 2013 Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 305 R459–R463. (https://doi.org/10.1152/ajpregu.00222.2013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yong LC, Kuller LH, Rutan G & Bunker C 1993 Longitudinal study of blood pressure: changes and determinants from adolescence to middle age. The Dormont High School follow-up study, 1957–1963 to 1989–1990. American Journal of Epidemiology 138 973–983. (https://doi.org/10.1093/oxfordjournals.aje.a116817)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu D, Holz S, Metzger E, Pavlovic M, Jandausch A, Jilg C, Galgoczy P, Herz C, Moser M & Metzger D et al.2014 Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells. Nature Communications 5 3174. (https://doi.org/10.1038/ncomms4174)

    • PubMed
    • Search Google Scholar
    • Export Citation