Role of 15-lipoxygenase in Enhanced Pulmonary Vasoconstriction in Females

描述（由申请人提供）：肺动脉高压包括一组以高肺动脉压和肺血管阻力为特征的疾病。血管收缩、血管重塑和血栓形成都有助于血管阻力增加。拟议研究的核心是，虽然相对罕见，但特发性肺动脉高压是一种医学上重要的疾病，更常见于年轻女性。这种疾病通常对患者是灾难性的。解释肺动脉高压性别差异的机制还没有得到很好的研究。目前建议的主要重点是使用兔子模型来探索性别在调节肺血管张力的新信号通路中的作用。本研究结果将为未来的研究奠定基本的概念基础，以更全面地了解女性肺动脉高压的发病机制。此外，这项工作旨在促进妇女健康研究和性别/性别差异研究的新概念。具体来说，我们的研究提供了第一个证据，即在从雌性家兔获得的肺动脉中，与雄性家兔的反应相比，对花生四烯酸和乙酰甲胆碱的内皮依赖性收缩增强。花生四烯酸代谢抑制剂的药理学研究表明，该因子是一种脂氧合酶代谢产物。我们还提出了第一个数据，脂氧合酶代谢物增加，女性相比，男性和15-脂氧合酶的蛋白质表达是女性肺动脉。虽然已经记录了对各种血管活性剂的血管反应的性别差异，但没有研究调查性别差异对肺动脉中AA的脂氧合酶代谢的作用。该建议旨在探讨特定的假设，即AA代谢的差异15-LO有助于增加内皮依赖性肺血管收缩的女性相比，男性。为了进一步发展这一新的假设，将使用化学、生物化学、生理学和药理学方法在肺动脉血管制备物中进行研究。将探索两个具体目标：1）对家兔肺动脉内皮产生的血管收缩剂15-脂氧合酶代谢物进行化学鉴定和生物学表征; 2）检查与雄性相比，导致雌性15-脂氧合酶表达增强的细胞机制。这些研究不仅为内源性花生四烯酸衍生因子在肺动脉高压发病机制中的作用提供了新的见解，而且还将通过确定导致肺动脉高压发病率性别差异的可能机制来提高我们在女性健康研究方面的知识。 公共卫生相关性：虽然相对罕见，但特发性肺动脉高压是一种医学上重要的疾病，更常见于年轻女性。这种疾病通常对患者是灾难性的。考虑到大量的临床数据表明血管疾病的性别差异，确定可能使女性易患肺动脉高压的内源性肺因素是及时和重要的。此外，这项工作旨在促进妇女健康研究和性别/性别差异研究的新概念。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension encompasses a group of diseases characterized by high pulmonary artery pressure and pulmonary vascular resistance. Vasoconstriction, vascular remodeling and thrombosis all contribute to the increased vascular resistance. Central to the proposed studies is that while relatively rare, idiopathic pulmonary arterial hypertension is a medically significant disease that occurs more frequently in young women. The disease is usually catastrophic for those afflicted. Mechanisms to explain the sex- difference in pulmonary arterial hypertension have not been well studied. The main focus of the current proposal is to use a rabbit model to explore the role of sex in a novel signaling pathway that regulates pulmonary vascular tone. Results will lay the fundamental conceptual groundwork for future studies to understand more completely the pathogenesis of pulmonary hypertension in women. Furthermore, this work is intended to advance new concepts in women's health research and the study of sex/gender differences. Specifically, our research provided the first evidence that in pulmonary arteries obtained from female rabbits, endothelium-dependent contractions to both arachidonic acid and methacholine were enhanced when compared to responses in males. Pharmacological studies with inhibitors of arachidonic acid metabolism indicated that the factor was a lipoxygenase metabolite. We also present the first data that lipoxygenase metabolites are increased in females compared to males and the protein expression of 15-lipoxygenase is greater in female pulmonary arteries. While sex differences in vascular responses to various vasoactive agents have been documented, no studies have investigated the role of sex differences on lipoxygenase metabolism of AA in pulmonary arteries. This proposal is designed to explore the specific hypothesis that differences in AA metabolism by 15-LO contribute to the increased endothelium-dependent pulmonary vasoconstriction in females compared to males. To further develop this novel hypothesis, studies will be performed in pulmonary artery vascular preparations using chemical, biochemical, physiological and pharmacological approaches. Two specific aims will be explored: 1) To chemically identify and biologically characterize the vasoconstrictor 15- lipoxygenase metabolite(s) produced by the rabbit pulmonary artery endothelium and 2) To examine the cellular mechanisms contributing to enhanced 15-lipoxygenase expression in females compared to males. These proposed studies will not only provide new insights into the role of endogenous arachidonic acid-derived factors in the pathogenesis of pulmonary arterial hypertension but will also advance our knowledge in women's health research by identifying possible mechanisms that contribute to sex-related differences in the incidence of pulmonary arterial hypertension. PUBLIC HEALTH RELEVANCE: While relatively rare, idiopathic pulmonary arterial hypertension is a medically significant disease that occurs more frequently in young women. The disease is usually catastrophic for those afflicted. Identifying endogenous pulmonary factors that may predispose females to the development of pulmonary hypertension is timely and important considering the abundance of clinical data indicating sex differences in vascular disease. Furthermore, this work is intended to advance new concepts in women's health research and the study of sex/gender differences.