PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease.
PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease.
复制标题
DOI：
--
复制
发表时间：
1999
期刊：
影响因子：
--
通讯作者：
N. Marx;T. Bourcier;G. Sukhova;P. Libby;J. Plutzky
中科院分区：
文献类型：
--
作者：
N. Marx;T. Bourcier;G. Sukhova;P. Libby;J. Plutzky
纤溶酶原激活物抑制剂1型（派-1）是一种主要的生理性纤溶抑制剂，其血浆水平与心肌梗死和静脉血栓形成的风险相关。内皮细胞（EC）是派-1的主要来源，其对派-1转录的调节仍不完全清楚。脂肪细胞也产生派-1，这表明脂肪细胞和EC之间可能存在共同的调节途径。过氧化物酶体增殖物激活受体-γ（PPAR）γ是一种配体激活的转录因子，可调节基因表达，以响应各种介质，如15-脱氧-Delta 12，14-前列腺素J2（15 d-PGJ 2）和氧化亚油酸（9-和13-HODE）。本研究测试的假设，人类内皮细胞表达PPARgamma和这种转录激活因子调节派-1在这种细胞类型的表达。我们发现人内皮细胞同时含有PPARgamma mRNA和蛋白质。人颈动脉的免疫组织化学也揭示了PPARgamma在EC中的存在。牛内皮细胞转染的PPAR反应元件（PPRE）-荧光素酶构建体响应于刺激的PPARgamma激动剂15 d-PGJ 2的浓度依赖性的方式，表明在内皮细胞的功能PPARgamma。用15 d-PGJ 2、9（S）-HODE或13（S）-HODE处理人EC可增加派-1 mRNA和蛋白表达，而多种PPARalpha激活剂不改变派-1水平。在人成纤维细胞中引入增加量的PPARgamma表达构建体增强了派-1从这些细胞中的分泌，与转染的DNA的量成比例。因此，EC表达调节EC中派-1表达的功能活性PPARgamma。我们的研究结果确立了PPARgamma在EC基因表达调控中的作用，对肥胖和动脉粥样硬化之间的临床联系具有重要意义。
Plasminogen activator inhibitor type-1 (PAI-1) is a major physiological inhibitor of fibrinolysis, with its plasma levels correlating with the risk for myocardial infarction and venous thrombosis. The regulation of PAI-1 transcription by endothelial cells (ECs), a major source of PAI-1, remains incompletely understood. Adipocytes also produce PAI-1, suggesting possible common regulatory pathways between adipocytes and ECs. Peroxisomal proliferator-activated receptor-gamma (PPAR)gamma is a ligand-activated transcription factor that regulates gene expression in response to various mediators such as 15-deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) and oxidized linoleic acid (9- and 13-HODE). The present study tested the hypotheses that human ECs express PPARgamma and that this transcriptional activator regulates PAI-1 expression in this cell type. We found that human ECs contain both PPARgamma mRNA and protein. Immunohistochemistry of human carotid arteries also revealed the presence of PPARgamma in ECs. Bovine ECs transfected with a PPAR response element (PPRE)-luciferase construct responded to stimulation by the PPARgamma agonist 15d-PGJ2 in a concentration-dependent manner, suggesting a functional PPARgamma in ECs. Treatment of human ECs with 15d-PGJ2, 9(S)-HODE, or 13(S)-HODE augmented PAI-1 mRNA and protein expression, whereas multiple PPARalpha activators did not change PAI-1 levels. Introduction of increasing amounts of a PPARgamma expression construct in human fibroblasts enhanced PAI-1 secretion from these cells in proportion to the amount of transfected DNA. Thus, ECs express functionally active PPARgamma that regulates PAI-1 expression in ECs. Our results establish a role for PPARgamma in the regulation of EC gene expression, with important implications for the clinical links between obesity and atherosclerosis.