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

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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