Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats.
Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats.
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DOI：
10.1161/hypertensionaha.112.191445
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发表时间：
2012-08
期刊：
影响因子：
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通讯作者：
Eghbali M
中科院分区：
文献类型：
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作者：
Matori H;Umar S;Nadadur RD;Sharma S;Partow-Navid R;Afkhami M;Amjedi M;Eghbali M
用植物雌激素染料木黄酮预处理已被证明可以减轻肺动脉高压（PH）的发展。由于PH并不总是早期诊断，我们研究了染料木黄酮是否也可以逆转预先存在的PH和预防相关的右心衰竭（RHF）。雄性大鼠用野百合碱60 mg/kg诱发PH。21天后，当PH良好建立时，大鼠接受每日注射染料木黄酮（每天1 mg/kg），持续10天，或不进行治疗，到第30天发展为RHF。观察染料木黄酮对体外培养的人肺动脉平滑肌细胞和内皮细胞增殖及新生大鼠心室肌细胞肥大的影响。野百合碱给药后21天出现严重的PH，右室收缩压峰值升高至66.35±1.03 mm Hg，右室射血分数降低至41.99± 1.27%。PH在第30天进展为RHF（右心室压，72.41 ± 1.87 mm Hg; RV射血分数，29.25 ± 0.88%），RHF大鼠的死亡率约为75%。金雀异黄素治疗后肺功能和心功能明显改善，右心室压力显著降低至43.34±4.08 mm Hg，右心室射血分数完全恢复至65.67 ± 1.08%，与对照组相似。Genistein在体内逆转PH诱导的肺血管重构，在体外抑制人肺动脉平滑肌细胞增殖达50%以上，可能通过雌激素受体-β发挥作用。染料木黄酮还逆转右心室肥大（右心室肥大指数为0.35±0.029，RHF为0.70±0.080），抑制新生大鼠心室肌细胞肥大，并恢复PH诱导的右心室毛细血管损失。心肺功能和结构的这些改善导致到第30天100%的存活率。染料木黄酮恢复PH诱导的右心室和肺中雌激素受体β表达的下调。总之，染料木黄酮治疗不仅挽救了既存的重度PH，而且还防止了重度PH向RHF的进展。
Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41 ± 1.87 mm Hg; RV ejection fraction, 29.25 ± 0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67 ± 1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-β. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF.