PROSTACYCLIN IN SYNTHESIS PULMONARY HYPERTENSION

在严重的肺动脉高压中，血管张力的调节是 血管的形态也发生了改变。我们发现了一个 血管扩张性前列腺素合成的相对缺陷 低氧性重症新生小牛的动脉而不是静脉 肺动脉高压。由于这一缺陷可以在 培养的血管内皮细胞和平滑肌细胞，甚至成纤维细胞 血管，我们希望研究这种缺陷的性质和机制 对这一缺陷负有责任。前列环素(PGI2)和前列腺素E_2 对血管张力调节很重要，而且具有抗增殖作用。我们 假设肺性(可能还有全身性)高血压 动脉表现为高血压细胞表型。我们进一步假设 PGI2合成能力的大幅下降是一个 这种高血压表型的重要特征。血流动力学应力 (压力增加，管壁拉伸)尖锐地诱导了 PGI2合成增加，随后是自杀失活 这种酶和由于酶再生受损，导致 慢性内源性前列腺素I2合成减少。我们计划研究 肺血管前列腺素I2合成受损的机制 高血压小牛和大鼠。(系统性高血压动脉也将 被研究)。可能有几个组件加在一起，构成了 高血压血管PG合成受损。最初的实验引领我们 相信在高血压细胞中，环氧合酶的产物 损害或失活PGI2合成酶的功能。我们计划 从牛、人和大鼠肺血管中提纯PGI2合成酶， 并测量细胞中PGI2合酶的质量和活性 高血压动脉。我们计划使用聚合酶链式反应(PCR) 克隆牛(人)肺内皮细胞的技术 细胞PGI2合成酶，获得氨基酸序列，并检测 正常血压和高血压患者前列腺素I2合成酶基因转录的研究 细胞。可诱导大鼠缺氧性肺动脉高压，其作用机制为 肺和肺动脉PGI2合成能力将在 N-乙酰半胱氨酸处理的大鼠组织(提高谷胱甘肽 抗氧化剂)、鱼油或钙离子进入阻滞剂。这些 策略可能导致内源性肺血管PGI2增加 合成，这反过来可能保护血管重塑。我们也 想要检查简单的机械扰动(血管环 收缩、拉伸、剪切应力)导致PGI2合成障碍 通过自杀使酶失活。

In severe pulmonary hypertension, the regulation of vascular tone is altered as well as the normal morphology of the vessels. We have found a relative deficiency in the synthesis of vasodilatory prostaglandins in the arteries but not veins of neonatal calves with hypoxia-induced severe pulmonary hypertension. Since this deficiency can be demonstrated in endothelial and smooth muscle cells and even fibroblasts cultured from vessels, we wish to study the nature of this defect and the mechanisms responsible for this deficiency. Prostacyclin (PGI2) and PGE2 are important for vascular tone regulation and are antiproliferative. We postulate that the pulmonary (and possibly systemic also) hypertensive arteries express a hypertensive cell phenotype. We further postulate that the substantial decrease in the PGI2 synthesis capacity is one important feature of this hypertensive phenotype. Hemodynamic stress (increased pressure, vessel wall stretch) acutely induces a large increase in PGI2 synthesis which is followed by suicide inactivation of the enzyme and because of impaired enzyme regeneration, leads to a chronic decrease in endogenous PGI2 synthesis. We plan to examine the mechanism of impaired PGI2 synthesis in arteries from pulmonary hypertensive calves and rats. (Systemic hypertensive arteries will also be studied). There are likely several components which add up to the impaired PG synthesis of hypertensive vessels. First experiments lead us to believe that in hypertensive cells, a product of the cyclooxygenase impairs or inactivates the function of the PGI2 synthase. We plan to purify the PGI2 synthase from bovine, human, and rat pulmonary vessels, and to measure the mass and activity of the PGI2 synthase in cells from hypertensive arteries. We plan to use polymerase chain reaction (PCR) technology to clone the bovine (and also human) pulmonary endothelial cell PGI2 synthase, to obtain the amino acid sequence, and to examine the transcription of the PGI2 synthase gene in normotensive and hypertensive cells. Hypoxic pulmonary hypertension will be induced in rats, and the lung and pulmonary artery PGI2 synthesis capacity will be assessed in tissues from rats treated with N-acetyl cysteine (to raise glutathione antioxidant defenses), fish oil, or a Ca4++-entry blocker. These strategies may lead to increased endogenous pulmonary vascular PGI2 synthesis, which in turn may protect against vascular remodeling. We also want to examine whether simple mechanical perturbations (vascular ring contraction, stretch, shear stress) cause impairment of PGI2 synthesis by suicide inactivation of the enzyme.