title: Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action.
abstract: The cellular responses to steroids are mediated by 2 general mechanisms: genomic and rapid/nongenomic effects. Identification of the mechanisms underlying aldosterone (ALDO)'s rapid vs their genomic actions is difficult to study, and these mechanisms are not clearly understood. Recent data suggest that striatin is a mediator of nongenomic effects of estrogen. We explored the hypothesis that striatin is an intermediary of the rapid/nongenomic effects of ALDO and that striatin serves as a novel link between the actions of the mineralocorticoid and estrogen receptors. In human and mouse endothelial cells, ALDO promoted an increase in phosphorylated extracellular signal-regulated protein kinases 1/2 (pERK) that peaked at 15 minutes. In addition, we found that striatin is a critical intermediary in this process, because reducing striatin levels with small interfering RNA (siRNA) technology prevented the rise in pERK levels. In contrast, reducing striatin did not significantly affect 2 well-characterized genomic responses to ALDO. Down-regulation of striatin with siRNA produced similar effects on estrogen's actions, reducing nongenomic, but not some genomic, actions. ALDO, but not estrogen, increased striatin levels. When endothelial cells were pretreated with ALDO, the rapid/nongenomic response to estrogen on phosphorylated endothelial nitric oxide synthase (peNOS) was enhanced and accelerated significantly. Importantly, pretreatment with estrogen did not enhance ALDO's nongenomic response on pERK. In conclusion, our results indicate that striatin is a novel mediator for both ALDO's and estrogen's rapid and nongenomic mechanisms of action on pERK and phosphorylated eNOS, respectively, thereby suggesting a unique level of interactions between the mineralocorticoid receptor and the estrogen receptor in the cardiovascular system.
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension (P.C., C.V., L.H.P., G.N.P., T.M.Y., G.A., M.T.-G., E.R.M., A.R.-R., J.S.W., G.W., J.R.R.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Laboratory Medicine (C.V., A.R., G.N.P., E.R.M.), Boston Children's Hospital and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Patricia
authors.initials: P
authors.lastname: Coutinho
authors.forename: Christopher
authors.initials: C
authors.lastname: Vega
authors.forename: Luminita H
authors.initials: LH
authors.lastname: Pojoga
authors.forename: Alicia
authors.initials: A
authors.lastname: Rivera
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Prado
authors.forename: Tham M
authors.initials: TM
authors.lastname: Yao
authors.forename: Gail
authors.initials: G
authors.lastname: Adler
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres-Grajales
authors.forename: Enrique R
authors.initials: ER
authors.lastname: Maldonado
authors.forename: Arelys
authors.initials: A
authors.lastname: Ramos-Rivera
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Williams
authors.forename: Gordon
authors.initials: G
authors.lastname: Williams
authors.forename: Jose R
authors.initials: JR
authors.lastname: Romero
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology; D047468:Immunoprecipitation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002148:Calmodulin-Binding Proteins; D004967:Estrogens; D006728:Hormones; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; C491924:Strn protein, mouse; D000450:Aldosterone