OR02-2 Aldosterone's Affect on Epigenetic Regulators and mTOR Signaling in the Heart

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR02-Renin-Angiotensin-Aldosterone - Bench to Bedside
Friday, April 1, 2016: 11:45 AM-1:15 PM
Presentation Start Time: 12:00 PM
Room 156 (BCEC)

Outstanding Abstract Award
Danielle L Cullinane*1, Amanda Elizabeth Garza1, Jose R Romero1, Gail K Adler2, Luminita H Pojoga1 and Gordon H Williams1
1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 2Brigham and Women's Hospital/Harvard Medical School, Boston, MA
Mammalian target of rapamycin (mTOR) has been linked to a variety of pathological outcomes including cardiovascular disease (CVD). Recently, it was reported that mTOR signaling is increased in patients with primary aldosteronism. Aldosterone (ALDO), and its mineralocorticoid receptor (MR) regulate salt/water homeostasis and blood pressure, and excess MR activity contributes to CVD. The epigenetic factors, lysine-specific demethylase 1 (LSD1/KDM1A) and NAD-dependent deacetylase sirtuin-1 (SIRT1) are known to negatively and positively, regulate mTOR signaling, respectively. LSD1 is part of a complex that binds to the mTOR promoter region, and represses gene expression. SIRT1 positively regulates mTORC1 function by inhibiting the acetylation of a downstream target; p70 ribosomal S6 kinase (S6K1). ALDO infusion has been shown to decrease SIRT1 expression in rat kidney. Furthermore, our group has shown that LSD1+/- mice have increased plasma ALDO relative to wildtype mice. Thus, we hypothesize that ALDO infusion will modulate LSD1, SIRT1, and mTOR signaling in cardiac tissue. To test this hypothesis, we studied C57/BL6 male mice maintained on a high salt (HS) diet (1.6% Na+). Mice were randomized to the following treatments for 3 weeks: 1) placebo, 2) ALDO (200µg/kg/day), or 3) ALDO + the mineralocorticoid receptor (MR) antagonist eplerenone (EPL), (100mg/µg/day). Animals were sacrificed and protein expression in cardiac tissue was analyzed by Western Blot. ALDO infusion was demonstrated to be effective by significantly decreased plasma renin activity (PRA) on both ALDO and EPL treated groups. ALDO treatment caused a significant 81% reduction in cardiac mTOR expression that was partially rescued by EPL treatment. The downstream targets of mTORC1 and mTORC2, S6K1 and Protein Kinase B (PKB/AKT) were not significantly modified in any treatment group. In contrast to mTOR expression, LSD1 was significantly increased (80%) in response to ALDO while EPL treatment blocked this effect. These data suggest that increases in LSD1 are mediated by ALDO/MR. Conversely, SIRT1 expression had a decreasing trend in response to ALDO infusion; and was significantly increased (90%) in response to EPL treatment. These data demonstrate that ALDO/MR modulates not only mTOR’s expression, but also the expression of LSD1 and SIRT1, consistent with the role of these epigenetic regulators in mTOR signaling. Thus, our data suggest that the substantial interaction between environmental factors and aldosterone’s adverse CV effects may be mediated by one or both of these epigenetic factors. Finally either these epigenetic regulators or other proteins in the mTOR pathway may prove to be promising new candidates linking ALDO and pathophysiological changes in CVD as well as potential therapeutic targets.

Disclosure: GHW: Ad Hoc Consultant, Daiichi Sankyo, Ad Hoc Consultant, Pfizer Global R&D. Nothing to Disclose: DLC, AEG, JRR, GKA, LHP

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting/pr-resources-for-endo

Sources of Research Support: The Ruth L. Kirschstein NRSA Institutional Research Training Grant (T32); National Institutes of Health NHLBI HL-69208; AHA 14GRNT20500000.