Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Pulmonary Hypertension Research Group, Institute Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Quebec City, Quebec, Canada.
J Clin Invest. 2021 Mar 15;131(6). doi: 10.1172/JCI129433.
Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α-null or ER-β-null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.
女性肺动脉高压 (PAH) 患者的右心室 (RV) 功能和存活率优于男性；然而，其潜在机制尚不清楚。我们假设，17β-雌二醇 (E2) 通过雌激素受体 α (ER-α)，通过依赖 BMPR2 的机制上调促收缩和促生存肽 Apelin，从而减轻 PAH 诱导的 RV 衰竭 (RVF)。我们发现，RVF 患者和适应性（而非适应性）RV 重构大鼠的 RV 匀浆中 ER-α 和 Apelin 的表达减少。E2 或 ER-α 激动剂处理后，RV 心肌细胞中的 Apelin 丰度在体内或体外增加。使用 ER-α 缺失或 ER-β 缺失小鼠、ER-α 功能丧失突变大鼠或 siRNA 的研究表明，ER-α 是 E2 上调 RV Apelin 所必需的。E2 和 ER-α 增加了肺动脉高压 RV 中的 BMPR2 和分离的 RV 心肌细胞中的 BMPR2，与 ER-α 结合到 Bmpr2 启动子有关。BMPR2 是 E2 介导的 Apelin 丰度增加所必需的，BMPR2 和 Apelin 都是 E2 发挥 RV 保护作用所必需的。E2 或 ER-α 激动剂挽救了野百合碱肺动脉高压，并恢复了 RV Apelin 和 BMPR2。我们确定了我们认为在 RV 中存在的一种新的心脏保护 E2/ER-α/BMPR2/Apelin 轴。利用这个轴可能会为男女 PAH 患者带来新的 RV 靶向治疗方法。
