Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones
Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones
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DOI：
10.1152/ajplung.00006.2015
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发表时间：
2015-05-01
影响因子：
4.9
通讯作者：
Lahm, Tim
中科院分区：
文献类型：
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作者：
Frump, Andrea L.;Goss, Kara N.;Lahm, Tim
雌激素是PAH的疾病调节剂。尽管女性患者的右心室（RV）功能优于男性，但雌激素对RV功能的影响（PAH生存的主要决定因素）尚未完全表征。我们试图确定在PAH的SuHx模型中RV功能是否存在性别差异，雌性动物的激素耗竭是否影响RV功能，以及E2补充是否改善RV适应。此外，我们研究了ER在介导E2的RV效应中的贡献。在雄性和雌性Sprague-Dawley大鼠以及OVX雌性大鼠中诱导SuHx诱导的肺动脉高压（SuHx-PH），伴随或不伴随E2补充（75 μ g . kg（-1）。天（-1））。雌性SuHx大鼠的CI优于雄性SuHx大鼠。OVX使SuHx诱导的CI降低和SuHx诱导的RVH和炎症（MCP-1和IL-6）增加恶化。在OVX大鼠中，E2补充减弱了SuHx诱导的RV收缩压（RVSP）、RVH和肺动脉重塑的增加，并改善了CI和运动能力（（V）超过点（O2 max））。此外，E2补充改善SuHx诱导的RV谷胱甘肽激活，促凋亡信号，细胞质糖酵解和促炎细胞因子表达的改变。SuHx-OVX组RV中ER α的表达降低，但在E2补充后恢复。RV ER α表达与RVSP和RVH呈负相关，与CO和apelin RNA水平呈正相关。在雌性中观察到的RV保护性E2效应在用E2或药理学ER α或ER β激动剂处理的雄性SuHx大鼠中重现。我们的数据表明，在严重PH模型中，E2具有显著的RV保护性ER介导作用。
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 mu g . 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 ((V) over dot(O2max)). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ER alpha in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ER alpha 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 ER alpha or ER beta agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.