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

内皮素1和性别差异在肺动脉高压发病机制中的作用

基本信息

批准号：
17590232
负责人：
MATSUMURA Yasuo
金额：
$ 2.4万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

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

1.缺氧(0-1% O_2)增加HIF-1α与ET-1_<HIF-1>寡核苷酸的结合虽然缺氧显着增强前原ET-1 mRNA表达，但ET-1从PAEC释放到培养基中显着。 ATP 消耗（抗霉素 A 和葡萄糖剥夺）对 HIF-1α 激活和 ET-1 产生的影响与缺氧条件下观察到的结果相似。另一方面，缺氧或 ATP 耗尽会增加 AMPK 磷酸化。此外，5-氨基咪唑-4-甲酰胺-1b-核糖苷 (AICAR)（被称为 AMPK 激活剂）可显着增强 HIF-1a 激活、prepro ET-1 mRNA 表达。和 AMPK 磷酸化，但显着降低了 PAEC 的 ET-1 释放，这些发现表明 ET-1 的产生低于 PAEC。缺氧条件不仅在转录水平上受到 HIF-1a 的调节，而且在翻译水平上也受到 AMPK 的调节。 2. 我们研究了野百合碱 (MCT) 诱导的肺动脉高压 (PH) 的性别差异是否由肝脏代谢引起。接受 MCT 的动物表现出严重的 PH，与右心室压力升高和肥大、肺动脉中层增厚以及 ET-1 水平相关。 MCT 引起的男性和女性之间的改变没有显着差异，而女性卵巢切除显着加重了上述病理变化，因此，我们认为雌性激素对女性中 MCT 引起的 PH 的发展具有保护作用。无论 MCT3 的代谢如何，我们研究了雷洛昔芬长期治疗对 MCT 诱导的大鼠 PH 的影响。雷洛昔芬长期治疗显着改善了 MCT 诱导的 PH 和相关器官。此外，雷洛昔芬的长期治疗显着抑制了右心室中 ET-1 的增加。这些结果表明，雷洛昔芬可防止 MCT 诱导的 PH 的发展，并对已建立的 PH 产生消退作用。