title: Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones.
abstract: Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2's RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Frump
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Kara N
authors.initials: KN
authors.lastname: Goss
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vayl
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Marjorie
authors.initials: M
authors.lastname: Albrecht
authors.affiliation: Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Amanda
authors.initials: A
authors.lastname: Fisher
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Roziya
authors.initials: R
authors.lastname: Tursunova
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: John
authors.initials: J
authors.lastname: Fierst
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Jordan
authors.initials: J
authors.lastname: Whitson
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Cucci
authors.affiliation: Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences;
authors.forename: M Beth
authors.initials: MB
authors.lastname: Brown
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana; and Richard L. Roudebush VA Medical Center, Indianapolis, Indiana tlahm@iu.edu.
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
mesh_terms: D000818:Animals; D000073861:Apelin; D017209:Apoptosis; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000096:biosynthesis; D047629:Estrogen Receptor beta / Q000819:agonists*; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology*; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D010052:Ovariectomy; D010053:Ovary / Q000601:surgery; D010805:Physical Conditioning, Animal; D011651:Pulmonary Artery / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D066253:Vascular Remodeling; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000073861:Apelin; C498579:Apln protein, rat; D016207:Cytokines; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D036341:Intercellular Signaling Peptides and Proteins; D004958:Estradiol
keywords: apoptosis; estrogen receptor; exercise capacity; right ventricular failure; sex differences