Role of endothelin-1 and gender difference in the pathogenesis of pulmonary hypertension

1.低氧(0-1%O_2)可增加HIF-1a与ET-1和lt；HIF-1和gt；尽管低氧显著增加前原ET-1mRNA的表达，但PAEC向培养液中释放的ET-1显著减少。ATP耗竭(抗霉素A和葡萄糖剥夺)对HIF-1a激活和ET-1产生的影响与低氧条件下的结果相似。另一方面，缺氧或ATP耗竭增加了AMPK的磷酸化。此外，AMPK激活剂5-氨基咪唑-4-甲酰胺-1b-核苷(5-氨基咪唑-4-甲酰胺-1b-核苷，AICAR)可显著增强PAECs的HIF-1a活化、ET-1前原mRNA表达和AMPK磷酸化，但显著减少PAECs释放ET-1。综上所述，这些发现表明，低氧条件下ET-1的产生不仅在转录水平上受到HIF-1a的调控，而且在翻译水平上也受到AMPK的调控。我们研究了野百合碱诱导的肺高压…是否存在性别差异更多的离子(PH)产生于MCT的肝脏代谢，并与ET-1的产生有关。接受MCT的动物表现出严重的PH，伴随着右室压力和肥厚的增加，肺动脉中层增厚，以及右室内的ET-1水平。男性和女性在MCT诱导的改变方面没有显著差异，而女性去卵巢显著加重了上述病理变化。因此，我们认为女性激素对MCT诱导的女性PH的发生具有保护作用，而与MCT3的代谢无关。我们观察了雷洛昔芬慢性治疗对MCT诱导的大鼠肺动脉高压的影响。雷洛昔芬慢性治疗可明显改善MCT所致的PH及相关脏器损害。此外，雷洛昔芬慢性治疗可显著抑制右室ET-1的升高。这些结果表明，雷洛昔芬可阻止MCT诱导的PH的发展，并对已建立的PH起到消退作用。较少

1. Hypoxia (0-1% O_2) increased binding of HIF-la to ET-1_<HIF-1> oligonucleotide. Although hypoxia significantly augmented prepro ET-1 mRNA expression, the ET-1 release from PAECs to the culture medium markedly decreased. The effects of ATP depletion (antimycin A and glucose deprivation) on HIF-la activation and ET-1 production were similar to results seen under hypoxic conditions. On the other hand, hypoxia or ATP depletion increased AMPK phosphorylation. In addition, 5-aminoimidazole-4-carboxamide-1b- riboside (AICAR), which is known as an activator of AMPK, significantly enhanced HIF-1a activation, prepro ET-1 mRNA expression, and AMPK phosphorylation, but markedly decreased the ET-1 release from PAECs. Taken together, these findings suggest that ET-1 production under hypoxic conditions is regulated by not only HIF-1a at a transcriptional level but also AMPK at a translational level.2. We investigated whether the gender differences in monocrotaline (MCT)-induced pulmonary hypertens … More ion (PH) result from the hepatic metabolism of MCT and are related to ET-1 production. Animals given MCT showed severe PH associated with increases in right ventricular pressure and hypertrophy, pulmonary arterial medial thickening, and ET-1 levels in right ventricle. There were no significant differences in MCT-induced alterations between males and females, whereas ovariectomy in females significantly aggravated the above pathologic changes. Thus, we suggest that female hormone have protective functions against the development of MCT-induced PH in females, irrespective of the metabolism of MCT3. We investigated the effects of chronic treatment with raloxifene on MCT-induced PH in rats. Chronic treatment with raloxifene significantly improved the MCT-induced PH and related organ damage. In addition, chronic treatments with raloxifene significantly suppressed the increment of ET-1 in right ventricle. These results indicate that raloxifene prevents the development of MCT-induced PH and exerts regressive effects on the established PH. Less