Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: Effects of endogenous and exogenous sex hormones

Andrea L. Frump, Kara N. Goss, Alexandra Vayl, Marjorie Albrecht, Amanda Fisher, Roziya Tursunova, John Fierst, Jordan Whitson, Anthony R. Cucci, M. Beth Brown, Tim Lahm

Research output: Contribution to journalArticle

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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<sup>-1</sup>·day<sup>-1</sup>). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHxinduced 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 (V˙ O<inf>2max</inf>). 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 ERα agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.

Original languageEnglish
Pages (from-to)L873-L890
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume308
Issue number9
DOIs
StatePublished - 2015

Fingerprint

Right Ventricular Function
Gonadal Steroid Hormones
Pulmonary Hypertension
Estradiol
Estrogens
Blood Pressure
Glycolysis
Ventricular Pressure
Carbon Monoxide
Sex Characteristics
Pulmonary Artery
Glutathione
Sprague Dawley Rats
Interleukin-6
Hormones
Pharmacology
RNA
Exercise
Cytokines
Inflammation

Keywords

  • Apoptosis
  • Estrogen receptor
  • Exercise capacity
  • Right ventricular failure
  • Sex differences

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension : Effects of endogenous and exogenous sex hormones. / Frump, Andrea L.; Goss, Kara N.; Vayl, Alexandra; Albrecht, Marjorie; Fisher, Amanda; Tursunova, Roziya; Fierst, John; Whitson, Jordan; Cucci, Anthony R.; Beth Brown, M.; Lahm, Tim.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 308, No. 9, 2015, p. L873-L890.

Research output: Contribution to journalArticle

Frump, Andrea L. ; Goss, Kara N. ; Vayl, Alexandra ; Albrecht, Marjorie ; Fisher, Amanda ; Tursunova, Roziya ; Fierst, John ; Whitson, Jordan ; Cucci, Anthony R. ; Beth Brown, M. ; Lahm, Tim. / Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension : Effects of endogenous and exogenous sex hormones. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015 ; Vol. 308, No. 9. pp. L873-L890.
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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 SuHxinduced 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 (V˙ O2max). 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 ERα agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.",
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AU - Fisher, Amanda

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