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

1. 缺氧（0-1% O_2）增加HIF-la与ET-1_< hif -1>寡核苷酸的结合。虽然缺氧显著增强了pre - pro ET-1 mRNA的表达，但PAECs向培养基释放的ET-1明显减少。ATP消耗（抗霉素A和葡萄糖剥夺）对HIF-la激活和ET-1产生的影响与缺氧条件下的结果相似。另一方面，缺氧或ATP消耗增加了AMPK的磷酸化。此外，被称为AMPK激活剂的5-氨基咪唑-4-羧酰胺-1b-核苷（AICAR）显著增强了HIF-1a的激活、pre - ET-1 mRNA的表达和AMPK的磷酸化，但显著降低了paec中ET-1的释放。综上所述，这些发现表明，缺氧条件下ET-1的产生不仅受HIF-1a转录水平的调控，还受AMPK翻译水平的调控。我们研究了单芥碱（MCT）诱导的肺动脉高压是否存在性别差异，更多的离子（PH）是由MCT的肝脏代谢引起的，并与ET-1的产生有关。给予MCT的动物表现出严重的PH值，右心室压力和肥厚增加，肺动脉内侧增厚，右心室ET-1水平升高。mct诱导的改变在男性和女性之间没有显著差异，而女性卵巢切除术明显加重了上述病理改变。因此，我们认为雌性激素对mct诱导的雌性PH的发展具有保护功能，而与MCT3的代谢无关。我们研究了雷洛昔芬慢性治疗对mct诱导的大鼠PH的影响。慢性雷洛昔芬治疗可显著改善mct诱导的PH和相关器官损伤。此外，慢性雷洛昔芬治疗可显著抑制右心室ET-1的增加。这些结果表明，雷洛昔芬可以阻止mct诱导的PH的发展，并对已建立的PH有倒退作用

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