title: Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy.
abstract: BACKGROUND
  Estrogen pretreatment has been shown to attenuate the development of heart hypertrophy, but it is not known whether estrogen could also rescue heart failure (HF). Furthermore, the heart has all the machinery to locally biosynthesize estrogen via aromatase, but the role of local cardiac estrogen synthesis in HF has not yet been studied. Here we hypothesized that cardiac estrogen is reduced in HF and examined whether exogenous estrogen therapy can rescue HF.
  
  
  RESULTS
  HF was induced by transaortic constriction in mice, and once mice reached an ejection fraction (EF) of ≈35%, they were treated with estrogen for 10 days. Cardiac structure and function, angiogenesis, and fibrosis were assessed, and estrogen was measured in plasma and in heart. Cardiac estrogen concentrations (6.18±1.12 pg/160 mg heart in HF versus 17.79±1.28 pg/mL in control) and aromatase transcripts (0.19±0.04, normalized to control, P<0.05) were significantly reduced in HF. Estrogen therapy increased cardiac estrogen 3-fold and restored aromatase transcripts. Estrogen also rescued HF by restoring ejection fraction to 53.1±1.3% (P<0.001) and improving cardiac hemodynamics both in male and female mice. Estrogen therapy stimulated angiogenesis as capillary density increased from 0.66±0.07 in HF to 2.83±0.14 (P<0.001, normalized to control) and reversed the fibrotic scarring observed in HF (45.5±2.8% in HF versus 5.3±1.0%, P<0.001). Stimulation of angiogenesis by estrogen seems to be one of the key mechanisms, since in the presence of an angiogenesis inhibitor estrogen failed to rescue HF (ejection fraction=29.3±2.1%, P<0.001 versus E2).
  
  
  CONCLUSIONS
  Estrogen rescues pre-existing HF by restoring cardiac estrogen and aromatase, stimulating angiogenesis, and suppressing fibrosis.
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Iorga
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Salil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Soban
authors.initials: S
authors.lastname: Umar
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Jean C
authors.initials: JC
authors.lastname: Bopassa
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Rangarajan D
authors.initials: RD
authors.lastname: Nadadur
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Centala
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Saito
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.) Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (L.T.).
authors.forename: Ligia
authors.initials: L
authors.lastname: Toro
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.) Department of Physiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (Y.W., E.S.).
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.) Department of Physiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (Y.W., E.S.).
authors.forename: Enrico
authors.initials: E
authors.lastname: Stefani
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA (A.I., J.L., S.S., S.U., J.C.B., R.D.N., A.C., S.R., T.S., L.T., Y.W., E.S., M.E.).
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D047629:Estrogen Receptor beta; D004958:Estradiol; D001141:Aromatase; D051057:Proto-Oncogene Proteins c-akt
keywords: angiogenesis; aromatase; estrogen; fibrosis; heart failure