HIF-1α-ET-1-L-PGDS通路调控缺氧诱导ANP分泌的作用研究

L-PGDS is a low-molecular mass glycoprotein that converts prostaglandin H2 into prostaglandin D2. More recently, it has been clarified a protective roles of L-PGDS in the heart under hypoxia and ischemia, the stabilization of the atherosclerotic plaque, acutely decompensated heart failure, hypertension, and stable coronary artery disease, and among others. However, the role of L-PGDS on the regulation of cardiac endocrine function is not known. Because of endothelin-1 (ET-1) is evoked arachdonic acid release to promotes prostaglandins synthesis by activation of its receptors and it is involved in the regulation of atrial natriuretic peptide (ANP) secretion, which plays inhibitory effect on the release of ET-1 as well as its roles. While, whether L-PGDS is involved in the processes of ET-1 on regulation of atrial ANP secretion is not clear. In previous study, we have observed that L-PGDS was involved in the action of endogenous ET-1 on the regulation of hypoxia-induced atrial ANP secretion and the effect was related with activation of ET receptors. However, the mechanism by which L-PGDS regulates hypoxia-induced atrial ANP secretion is not understood. The present project, therefore, is to investigate the effect of HIF-1α-ET-1-L-PGDS pathway on regulation of hypoxia-induced atrial ANP secretion and to provide the necessary theoretical and experimental basis for clarify role of L-PGDS on the heart endocrine functions under hypoxic condition. The results of the present project might provide a novel strategy to pharmacological or biologic interventions targeting positive modulation of L-PGDS production and selective controlling of arachidonic acid metabolism for cardiovascular diseases therapy.

Lipocalin型前列腺素D合成酶（L-PGDS）是一种低分子糖蛋白，它可催化前列腺素H2转变成前列腺素D2。研究表明，L-PGDS对缺血/缺氧心脏、失代偿性心衰、高血压、动脉粥样硬化及冠脉疾病等均具有保护作用。然而，L-PGDS对心脏内分泌功能的作用不清楚。由于内皮素-1（ET-1）不仅可诱导花生四希酸的释放，而且还可通过其受体促进前列腺素的生成，并介导ANP的分泌，而L-PGDS是否参与其中尚不清楚。在本课题的前期工作中发现，L-PGDS介导内源性ET-1调控缺氧诱导ANP分泌的过程，其作用受内皮素受体的调节，但其详细机制不清楚。因此，本课题主要探讨L-PGDS调控缺氧诱导ANP分泌的影响，揭示HIF-1α-ET-1-L-PGDS通路调控缺氧诱导ANP分泌的作用，为阐明L-PGDS对缺氧下心脏内分泌功能的作用和药理或生物干预L-PGDS的生成、调控花生四烯酸的代谢提供新的思路。

Lipocalin型前列腺素D合成酶（L-PGDS）是一种低分子糖蛋白，它可催化前列腺素H2转变成前列腺素D2（PGD2）。L-PGDS可抵制缺血/缺氧心脏、失代偿性心衰、高血压、动脉粥样硬化及冠状动脉疾病等并发挥重要保护作用。然而，L-PGDS对心脏内分泌功能的作用不清楚。在本课题的前期工作中发现，L-PGDS介导内源性ET-1调控缺氧诱导ANP分泌的过程，其作用受内皮素受体的调节，但其详细机制不清楚。因此，本课题主要探讨缺氧对心房L-PGDS表达的影响及其调节缺氧诱导ANP分泌的信号转导机制；弄清缺氧时L-PGDS对ET-1调节心房ANP分泌的作用及其机理；明确HIF-1α–ET-1–L-PGDS路径对缺氧诱导ANP分泌的作用；探讨缺氧时炎症和氧化应激对ANP分泌的影响及其与L-PGDS的相互关系。经研究发现，缺氧时接受HIF-1α调控的内源性ET-1通过其两种受体不仅增加心房IL-18的生成，而且还增强NADPH氧化酶4（NOX4）的活性。此时，在COX2的作用下通过激活L-PGDS和Nrf2增加PGD2生成及其代谢活化PPARγ；或ET-1诱导的NOX4可通过Src–IL-18路径激活ATF3和TCF3/及TCF4/ELF；或NOX4–Src路径通过ERK1/2及Akt活化GATA4，进而促进心房ANP的分泌。另外，NOX4–Sirt1–Nrf2途径也可通过ATF3和ATF4活化TCF3/及TCF4/ELF参与调节缺氧时ANP的分泌过程。由于L-PGDS及ANP均具有抗炎和抗氧化作用，故认为缺氧时提高L-PGDS活性并促进心房ANP的分泌是抵制炎症和氧化应激，促使细胞适应缺氧环境和保护心肌细胞的一种具体功能性表现。本课题的研究结果对进一步了解内源性ET-1的作用机理，深入研究和探讨ANP的分泌机制及其功能，以干预和诊治缺氧性及ET-1相关疾病等具有重要生物学意义。