Duelling receptors: estrogen receptor versus mineralocorticoid receptor in the cardiovascular system.

Abstract

here are times when investigators pursuing 2 distinctlines of research that address a common topic appeartobeoperatinginaparalleluniverse.Anyonewhohasservedin a grant review process will have pondered the irony of aseriesofgrantapplicationsaddressingthesamequestionbutvia different approaches or biological systems, each con-vincedtheirsisthekeypathwaywhilesteadfastlyignoringallother approaches. This has arguably been true of the workaddressing the role of steroid hormones in cardiovasculardisease,ormorespecificallycardiacfibrosis.Forsomeyears,thebeneficialeffectsofestrogenhavebeenextensivelychar-acterizedwithrespectnotonlytovascularreactivitybutalsofibrosis (1–3). The clinical correlate is of course the relativeprotection against cardiovascular disease in premenopausalwomen that is lost after the menopause. In the parallel uni-verse, a number of groups, including our own, have proveddetailedcharacterizationofthemolecularmechanismsdriv-ingtheproinflammatory,profibroticconsequencesofexcessmineralocorticoid receptor (MR) activation, be it by aldo-steroneorcortisol/corticosterone(reviewedinRef.4).Thesestudies,aswiththoseforestrogen,haveastrongclinicalcon-nection exemplified by the excess adverse consequences ofhyperaldosteronism, where the cardiovascular complica-tions of hypertension are clearly worse for the equivalentrises in blood pressure with hyperaldosteronism than forother causes of hypertension (5). This key role of MR acti-vation is further confirmed by a series of clinical trials thathave demonstrated improved outcomes for cardiac failurewhereanMRantagonistisaddedtoconventionaltherapy(6).The initial report of a pathophysiological role for ad-renalhormonesinvascularinflammationandfibrosiswasmadebyHansSeylein1946,butthisfindingwasnotfullyappreciated until Brilla and Weber in 1992 stimulated in-terestintheroleofaldosteroneincardiacfibrosis(4).Thesubsequent studies not only established a role for activa-tion of the MR, independent of hypertension and hyper-trophy, in cardiovascular inflammation and fibrosis butalso identified MR, activated by aldosterone, deoxycor-ticosterone, or cortisol/corticosterone, as the critical me-diator. More recent studies from our group and othershave dissected the tissue specificity of the response usingtissue-selective MR-null mice with key roles attributed tothe vascular MR (endothelial and smooth muscle cells)together with cardiomyocytes and cells of the monocyte/macrophagelineage(4).Ararelyacknowledgedsubtextinthese various rodent studies is that they are almost inev-itably performed in male animals, with the explanationbeing: “the response is more robust,” blinkered thinkingthat perhaps hides a critical biological significance. Morerecently, recognition has emerged that both experimen-tally and clinically sex-selective differences in the re-sponsestomineralocorticoidexcessandindeedmineralo-corticoid antagonist therapy need to be considered (7).Studiesusingarangeofanimalmodelsofvascularinjuryand/or cardiac fibrosis report exacerbation by aldosteroneand attenuation by estrogen (8), albeit almost never in thesamestudy.Arias-Lozaetal(9)directlyexaminedthisques-tion,findingthatestradiol(E2)actingthroughbothestrogenreceptors (ERs), ER and ER , was able to attenuate aldo-sterone-induced cardiovascular remodeling in salt-treatedrats. Pedram et al (1) have reported a critical role for ER -specific agonists in the prevention of cardiac hypertrophyand progression to cardiac fibrosis in female mice. This