17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension
17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension
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DOI：
10.1152/ajplung.00132.2016
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发表时间：
2016-08-01
影响因子：
4.9
通讯作者：
Brown, M. Beth
中科院分区：
文献类型：
--
作者：
Lahm, Tim;Frump, Andrea L.;Brown, M. Beth
17 β-雌二醇（E-2）对肺动脉高压（PAH）时的右心室（RV）功能具有保护作用。由于急性运动引起的后负荷增加可能导致PAH患者的RV功能障碍，我们试图确定E-2是否可以在急性运动挑战后实现上级RV适应。我们研究了Sugen/缺氧（SuHx）诱导的肺动脉高压雄性和雌性大鼠以及卵巢切除（OVX）SuHx雌性大鼠在以75%的个体测定的最大有氧能力（75%有氧能力储备）跑步机跑步45分钟后立即伴随或不伴随E-2补充（75 mug.kg（-1）.day（-1））的RV功能的超声心动图、血流动力学、结构和生化标志物。与雄性大鼠相比，完整的雌性大鼠表现出更高的每搏输出量和心脏指数，更好的RV顺应性的强烈趋势，以及指数化的总肺阻力增加不太明显。OVX取消了有利的RV适应，而E2在OVX后明显改善RV功能。E-2对肺血管重构的影响是复杂的，并且不如其RV效应那么稳健。内源性或外源性E-2的女性运动后血流动力学与非运动对照组的血流动力学相似，而OVX大鼠表现出更严重的运动后血流动力学改变。E-2介导对RV纤维化的抑制作用，并减弱RV胶原蛋白I/III比率的增加。促凋亡信号，内皮型一氧化氮合酶磷酸化，自噬通量标记物的影响，E-2耗竭和/或充盈。自噬通量受损的标志物与RV结构和功能的终点相关。内源性和外源性E-2对急性运动后即刻测量的RV功能产生保护作用。利用E-2的机制可能会导致新的RV导向疗法。
17 beta-Estradiol (E-2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E-2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E-2 repletion (75 mu g.kg(-1).day(-1)) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E-2 repletion after OVX markedly improved RV function. E-2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E-2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E-2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E-2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E-2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E-2's mechanisms may lead to novel RV-directed therapies.