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首页> 外文期刊>Pulmonary Circulation >Histone Deacetylase Inhibition with Trichostatin a does not Reverse Severe Angioproliferative Pulmonary Hypertension in Rats (2013 Grover Conference Series):
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Histone Deacetylase Inhibition with Trichostatin a does not Reverse Severe Angioproliferative Pulmonary Hypertension in Rats (2013 Grover Conference Series):

机译：曲古抑菌素a抑制组蛋白脱乙酰基酶不能逆转大鼠严重血管增生性肺动脉高压（2013年格罗弗会议系列）：

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Pulmonary arterial hypertension (PAH) is a rapidly progressive and devastating disease characterized by remodeling of lung vessels, increased pulmonary vascular resistance, and eventually right ventricular hypertrophy and failure. Because histone deacetylase (HDAC) inhibitors are agents hampering tumor growth and cardiac hypertrophy, they have been attributed a therapeutic potential for patients with PAH. Outcomes of studies evaluating the use of HDAC inhibitors in models of PAH and right ventricular pressure overload have been equivocal, however. Here we describe the levels of HDAC activity in the lungs and hearts of rats with pulmonary hypertension and right heart hypertrophy or failure, experimentally induced by monocrotaline (MCT), the combined exposure to the VEGF-R inhibitor SU5416 and hypoxia (SuHx), and pulmonary artery banding (PAB). We show that HDAC activity levels are reduced in the lungs of rat with experimentally induced hypertension, whereas activity levels are increased in the hypertrophic hearts. In contrast to what was previously found in the MCT model, the HDAC inhibitor trichostatin A had no effect on pulmonary vascular remodeling in the SuHx model. When our results and those in the published literature are taken together, it is suggested that the effects of HDAC inhibitors in humans with PAH and associated RV failure are, at best, unpredictable. Significant progress can perhaps be made by using more specific HDAC inhibitors, but before clinical tests in human PAH can be undertaken, careful preclinical studies are required to determine potential cardiotoxicity.
机译：肺动脉高压（PAH）是一种快速进行性和破坏性疾病，其特征是肺血管重构，肺血管阻力增加以及最终右心室肥大和衰竭。由于组蛋白脱乙酰基酶（HDAC）抑制剂是阻碍肿瘤生长和心脏肥大的药物，因此被认为对PAH患者具有治疗潜力。然而，评估在PAH和右心室压力超负荷模型中使用HDAC抑制剂的研究结果尚不清楚。在这里，我们描述了由单肾上腺素（MCT），VEGF-R抑制剂SU5416和低氧（SuHx）联合暴露诱发的患有肺动脉高压和右心肥大或衰竭的大鼠的肺和心脏中HDAC活性的水平，以及肺动脉束带（PAB）。我们显示，在实验性诱发的高血压大鼠的肺中，HDAC的活性水平降低，而在肥厚的心脏中，HDAC的活性水平升高。与以前在MCT模型中发现的相反，HDAC抑制剂曲古抑菌素A对SuHx模型中的肺血管重构没有影响。将我们的结果与已发表文献中的结果结合在一起时，表明HDAC抑制剂对PAH和相关RV衰竭患者的作用充其量是不可预测的。通过使用更特异性的HDAC抑制剂也许可以取得重大进展，但是在进行人类PAH的临床测试之前，需要进行仔细的临床前研究以确定潜在的心脏毒性。

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