Liu Aiping, Schreier David, Tian Lian, Eickhoff Jens C, Wang Zhijie, Hacker Timothy A, Chesler Naomi C
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin;
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin;
Am J Physiol Heart Circ Physiol. 2014 Aug 1;307(3):H273-83. doi: 10.1152/ajpheart.00758.2013. Epub 2014 Jun 6.
Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction and failure. Paradoxically, women are more frequently diagnosed with PAH but have better RV systolic function and survival rates than men. The mechanisms by which sex differences alter PAH outcomes remain unknown. Here, we sought to study the role of estrogen in RV functional remodeling in response to PAH. The SU5416-hypoxia (SuHx) mouse model of PAH was used. To study the role of estrogen, female mice were ovariectomized and then treated with estrogen or placebo. SuHx significantly increased RV afterload and resulted in RV hypertrophy. Estrogen treatment attenuated the increase in RV afterload compared with the untreated group (effective arterial elastance: 2.3 ± 0.1 mmHg/μl vs. 3.2 ± 0.3 mmHg/μl), and this was linked to preserved pulmonary arterial compliance (compliance: 0.013 ± 0.001 mm(2)/mmHg vs. 0.010 ± 0.001 mm(2)/mmHg; P < 0.05) and decreased distal muscularization. Despite lower RV afterload in the estrogen-treated SuHx group, RV contractility increased to a similar level as the placebo-treated SuHx group, suggesting an inotropic effect of estrogen on RV myocardium. Consequently, when compared with the placebo-treated SuHx group, estrogen improved RV ejection fraction and cardiac output (ejection fraction: 57 ± 2% vs. 44 ± 2% and cardiac output: 9.7 ± 0.4 ml/min vs. 7.6 ± 0.6 ml/min; P < 0.05). Our study demonstrates for the first time that estrogen protects RV function in the SuHx model of PAH in mice directly by stimulating RV contractility and indirectly by protecting against pulmonary vascular remodeling. These results underscore the therapeutic potential of estrogen in PAH.
肺动脉高压（PAH）会导致右心室（RV）功能障碍和衰竭。矛盾的是，女性比男性更常被诊断出患有PAH，但右心室收缩功能和生存率却比男性更好。性别差异改变PAH预后的机制尚不清楚。在此，我们试图研究雌激素在PAH引起的右心室功能重塑中的作用。使用了PAH的SU5416-低氧（SuHx）小鼠模型。为了研究雌激素的作用，对雌性小鼠进行卵巢切除，然后用雌激素或安慰剂进行治疗。SuHx显著增加了右心室后负荷并导致右心室肥大。与未治疗组相比，雌激素治疗减轻了右心室后负荷的增加（有效动脉弹性：2.3±0.1 mmHg/μl对3.2±0.3 mmHg/μl），这与肺动脉顺应性的保留有关（顺应性：0.013±0.001 mm²/mmHg对0.010±0.001 mm²/mmHg；P<0.05）以及远端肌化减少。尽管雌激素治疗的SuHx组右心室后负荷较低，但右心室收缩性增加到与安慰剂治疗的SuHx组相似的水平，表明雌激素对右心室心肌有正性肌力作用。因此，与安慰剂治疗的SuHx组相比，雌激素改善了右心室射血分数和心输出量（射血分数：57±2%对44±2%，心输出量：9.7±0.4 ml/min对7.6±0.6 ml/min；P<0.05）。我们的研究首次证明，雌激素在小鼠PAH的SuHx模型中通过直接刺激右心室收缩性和间接防止肺血管重塑来保护右心室功能。这些结果强调了雌激素在PAH中的治疗潜力。
