LEUKOTRIENES, PROSTACYCLIN, BLOOD VESSELS

据报道，自发性高血压大鼠（SHR） 类花生酸的几种酶系统异常 新陈代谢. 这些异常包括：1）增强的血管 磷脂酶A2（PLA 2）活性; 2）增强肾细胞色素 P450酶活性：3）尿PGF 2 α分泌增加; 4)血管PGI 2的产生增加; 5）产生增加 血小板12-脂氧合酶诱导的12-HETE。 然而，课程 SHR中这些异常的机制仍然存在， 未知 在这个建议中，我们将评估关键酶 负责产生和转化这些 类花生酸 将进行以下实验： 1.自发性高血压大鼠血管和肾脏磷脂酶A_2活性的研究 以及它们与高血压发展的关系。 2. 12-HPETE和15-HPETE转化的研究 通过酶“过氧化氢裂解酶”产生 C-12和C-14短链醛及其合成研究 生物活动。 3.血管中11-酮还原酶活性的研究 与SHR肾脏组织中9 α，11 β- SHR尿中PGF 2替代PGF 2 α。 4.血管“环加氧酶（PGH-synthase）”的研究 和“PGI 2-合酶”活性和酶水平， SHR。 5.研究了PGI_2通过氧化还原反应转化为5（6）-氧化-PGI_2。 细胞色素P450环氧合酶系统 6.的分子和细胞生物学研究 “环氧合酶”。 在这项特殊的研究中，肾脏细胞色素 来自SHR和WKY的P450环氧合酶和抗P450的特异性抗体 将产生环氧合酶。 转录和/或 表氧化酶基因的翻译将通过北方-和 Western dot-blot技术与肾cDNA克隆，这将 在研究过程中做好准备。 了解的机制，酶的水平和 SHR中这些酶系统的遗传调节可能导致 高血压的发展和防治。

It has been reported that spontaneously hypertensive rats (SHR) have abnormalities of several enzyme systems of eicosanoid metabolism. These abnormalities include: 1) enhanced vascular phospholipase A2 (PLA2) activity; 2) enhanced renal cytochrome P450 enzyme activity; 3) increased output of urinary PGF2alpha; 4) enhanced production of vascular PGI2; 5) increased production of 12-HETE by platelet 12-lipoxygenase. However, the courses and mechanisms involved in these abnormalities in SHR remain unknown. In this proposal we will evaluate the key enzymes responsible for the generation and transformation of these eicosanoids. The following experiments will be performed: 1. Studies on the vascular and renal PLA2 activities of SHR and their relationship to the development of hypertension. 2. Studies of the transformation of 12-HPETE and 15-HPETE by the enzyme "Hydroperoxide Lyase" for the generation of C-12 and C-14 short chain aldehydes and studies of their biological activities. 3. Studies of the activity of 11-ketoreductase in blood vessels and kidney of SHR and the occurance of 9alpha, 11beta- PGF2 instead of PGF2alpha in the urine of SHR. 4. Studies of the vascular "cyclo-oxygenase (PGH-synthase)" and "PGI2-synthase" activities and the enzyme levels in SHR. 5. Studies of the conversion of PGI2 to 5(6)-oxido-PGI2 via the cytochrome P450 epoxygenase system in SHR. 6. Studies of the molecular and cellular biology of "epoxygenase" in SHR. In this particular study, characterization of the renal cytochrome P450 epoxygenase from SHR and WKY and specific antibodies to epoxygenase will be made. Changes in transcription and/or translation of epoxygenase genes will be shown by Northern- and Western dot-blot technique with a renal cDNA clone, which will be prepared in the course of this study. The understanding of the mechanism, enzyme levels and the genetic regulation of these enzyme systems in SHR may lead to the development and treatment for prevention of hypertension.