Morimoto Shinji, Fujioka Yoshio, Hosoai Hiroshi, Okumura Takahiro, Masai Miho, Sakoda Tsuyoshi, Tsujino Takeshi, Ohyanagi Mitsumasa, Iwasaki Tadaaki
Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine, Nishinomiya, Japan.
Hypertens Res. 2003 Apr;26(4):315-23. doi: 10.1291/hypres.26.315.
Triglyceride-rich lipoproteins have been suggested to promote atherosclerosis. Plasminogen activator inhibitor type 1 (PAI-1) plays an important role in the events of cardiovascular pathophysiology. The renin-angiotensin system influences various vascular functions, including PAI-1 production. We examined whether or not chylomicron remnants increased PAI-1 mRNA and protein production in endothelial cells and whether or not an inhibition of the renin-angiotensin system interfered with this effect. Chylomicron remnants were isolated from functionally hepatectomized rats injected with chylomicrons. Human umbilical vein endothelial cell cultures (HUVECs) were incubated with chylomicron remnants with or without an angiotensin-converting enzyme inhibitor (temocaprilat), an angiotensin II receptor type 1 antagonist (RNH-6270), or an angiotensin II receptor type 2 antagonist (PD123319). Chylomicron remnants increased PAI-1 secretion in HUVECs (0.5 microg/ml; 128.3 +/- 6.1%, the mean +/- SEM) as well as angiotensin II (10 nmol/l; 130.7 +/- 9.5%) in 18 h, as compared with the controls, as well as stimulated PAI-1 mRNA expression to a maximum level at 4 h. Temocaprilat and RNH-6270, but not PD123319, attenuated all of these effects. Chylomicron remnants enhanced nuclear extract binding to a very low-density lipoprotein response element in the PAI-1 promoter region and activated nuclear factor-kappaB. Extracellular signal-regulated kinase (ERK 1/2) was phosphorylated in response to chylomicron remnants. These effects were inhibited by temocaprilat or RNH-6270. In conclusion, chylomicron remnants increased protein secretion and mRNA expression of PAI-1 in HUVECs. Inhibition of the renin-angiotensin system reduced this stimulation.
富含甘油三酯的脂蛋白被认为可促进动脉粥样硬化。纤溶酶原激活物抑制剂1（PAI-1）在心血管病理生理过程中发挥重要作用。肾素-血管紧张素系统影响多种血管功能，包括PAI-1的产生。我们研究了乳糜微粒残粒是否会增加内皮细胞中PAI-1 mRNA和蛋白的产生，以及肾素-血管紧张素系统的抑制是否会干扰这种作用。从注射了乳糜微粒的功能性肝切除大鼠中分离出乳糜微粒残粒。将人脐静脉内皮细胞培养物（HUVECs）与乳糜微粒残粒一起孵育，同时加入或不加入血管紧张素转换酶抑制剂（替莫卡普利）、1型血管紧张素II受体拮抗剂（RNH-6270）或2型血管紧张素II受体拮抗剂（PD123319）。与对照组相比，乳糜微粒残粒在18小时内增加了HUVECs中PAI-1的分泌（0.5微克/毫升；128.3±6.1%，平均值±标准误）以及血管紧张素II（10纳摩尔/升；130.7±9.5%），并在4小时时将PAI-1 mRNA表达刺激至最高水平。替莫卡普利和RNH-6270，但不是PD123319，减弱了所有这些作用。乳糜微粒残粒增强了核提取物与PAI-1启动子区域中极低密度脂蛋白反应元件的结合，并激活了核因子-κB。细胞外信号调节激酶（ERK 1/2）因乳糜微粒残粒而被磷酸化。这些作用被替莫卡普利或RNH-6270抑制。总之，乳糜微粒残粒增加了HUVECs中PAI-1的蛋白分泌和mRNA表达。肾素-血管紧张素系统的抑制减少了这种刺激。
