title: Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension.
abstract: Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg(-1)·day(-1), 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β.
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, University of California at Los Angeles, Los Angeles, California 90095-7115, USA.
authors.forename: Rangarajan D
authors.initials: RD
authors.lastname: Nadadur
authors.forename: Soban
authors.initials: S
authors.lastname: Umar
authors.forename: Gabriel
authors.initials: G
authors.lastname: Wong
authors.forename: Mansour
authors.initials: M
authors.lastname: Eghbali
authors.forename: Andrea
authors.initials: A
authors.lastname: Iorga
authors.forename: Humann
authors.initials: H
authors.lastname: Matori
authors.forename: Rod
authors.initials: R
authors.lastname: Partow-Navid
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004958:Estradiol / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000819:agonists; D047629:Estrogen Receptor beta / Q000819:agonists; D005109:Extracellular Matrix / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D016686:Monocrotaline / Q000633:toxicity; D009570:Nitriles / Q000494:pharmacology; D053495:Osteopontin / Q000096:biosynthesis; D010636:Phenols / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008565:Membrane Proteins; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; C506897:Spp1 protein, rat; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D053495:Osteopontin; D000804:Angiotensin II; D004958:Estradiol; D016686:Monocrotaline; D051722:ADAM Proteins; C490901:Adam15 protein, rat; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat