PROSTACYCLIN IN SYNTHESIS PULMONARY HYPERTENSION

在严重的肺动脉高压中，血管张力的调节是 血管的正常形态也发生了改变。 我们找到了一个 血管舒张素合成的相对缺乏， 新生犊牛的动脉，而不是静脉缺氧引起的严重 肺动脉高压 由于这种缺陷可以在 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， 对这一缺陷负责。 前列环素（PGI 2）和PGE 2是 对血管张力调节很重要且具有抗增殖作用。 我们 假设肺部（也可能是全身）高血压 动脉表达高血压细胞表型。 我们进一步假设 PGI 2合成能力的大幅下降是一个 这种高血压表型的重要特征。 血流动力学应激 （压力增加，血管壁拉伸）急性诱导大的 PGI 2合成增加，随后自杀失活， 由于酶再生受损，导致 内源性PGI 2合成的慢性减少。 我们计划研究 肺动脉PGI_2合成障碍的机制 高血压小牛和大鼠。（全身性高血压动脉也将 研究）。 可能有几个组成部分加起来， 高血压血管PG合成受损。 最初的实验让我们 相信在高血压细胞中，环氧合酶的产物 损害或失活PGI 2合酶的功能。 我们计划 从牛、人和大鼠肺血管中纯化PGI 2合酶， 并测量细胞中PGI 2合酶的质量和活性， 高血压动脉 我们计划使用聚合酶链反应（PCR） 克隆牛（以及人）肺内皮细胞的技术 细胞PGI 2合酶，以获得氨基酸序列，并检查 正常血压和高血压患者PGI 2合酶基因的转录 细胞 将在大鼠中诱导低血压性肺动脉高压， 将评估肺和肺动脉PGI 2合成能力， 用N-乙酰半胱氨酸处理的大鼠组织（以提高谷胱甘肽 抗氧化剂防御）、鱼油或Ca 4 ++进入阻滞剂。 这些 策略可能导致内源性肺血管PGI 2增加 合成，这反过来可以防止血管重塑。我们也 我想检查是否有简单的机械扰动（血管环 收缩、拉伸、剪切应力）导致PGI 2合成受损 通过酶的自杀性失活。

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.