前列腺素E_1对损伤血管内皮细胞的保护作用及其机制探讨
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摘要
血管内皮病变是心血管疾病发生的关键环节,氧化应激和炎症损伤是引起血管内皮损伤的两大主要原因。前列腺素E1(Prostaglandin E1, PGE1)是一种具有广泛生物活性的内源性物质,是多不饱和脂肪酸二高γ-亚油脂酸(DGLA)的氧化产物。PGE1具有舒张血管、抑制血小板聚集、促进血管新生和降低血液粘度的作用。临床上广泛用于冠状动脉粥样硬化性心脏病、心力衰竭、脑梗死、肺心病、肺动脉高压、糖尿病并发症、肾病等的治疗。现在越来越多的研究开始探索PGE1的抗炎抗氧化和血管内皮保护作用。PGE1可以保护人视网膜色素上皮细胞避免氧化损伤,抑制甲氨蝶呤处理大鼠肠粘膜上皮细胞产生活性氧(ROS),降低外周血管疾病、外周动脉硬化症和肝缺血再灌注损伤患者血液循环中的可溶性黏附分子。但是,还没有直接证据证明PGE1对损伤的内皮细胞具有保护作用。
本实验分别采用过氧化氢(H2O2)和肿瘤坏死因子-α(TNF-α)作为外源性自由基和炎症因子生成系统,模拟人脐静脉内皮细胞(HUVECs)的脂质过氧化损伤和炎症损伤过程,建立离体培养的HUVECs氧化损伤和炎症损伤模型,观察PGE1对氧化损伤和炎症损伤的HUVECs的保护作用,并探讨其可能机制,为其用于心、脑血管疾病的治疗提供药理学依据。
我们首先探讨PGE1对氧化损伤HUVECs的保护作用,发现：(1)H2O2(200μM)能显著降低HUVECs细胞的活力,诱导细胞凋亡,可作为体外模型模拟氧自由基致HUVECs细胞氧化应激损伤；(2)PGE1可显著增高H2O2损伤的HUVECs的细胞活力,抑制细胞内LDH释放；(3)PGE1能够启动HUVECs细胞内抗氧化防御机制,显著减少MDA的生成量,提高细胞内SOD的活性和GSH-Px的含量,清除细胞内的ROS；(4)PGE1对H2O2诱导的HUVECs细胞凋亡有明显抑制作用,可抑制凋亡细胞染色质形态学的变化,降低细胞凋亡率；(5)PGE1可提高H2O2损伤的HUVECs细胞的NO水平、eNOS mRNA和蛋白质的水平。由此可见,PGE1能够保护H2O2损伤的血管内皮细胞,NO途径在该过程中发挥重要作用。
我们接着探讨PGE1对炎症损伤HUVECs细胞的保护作用,发现：(1)TNF-a (10ng/ml)能显著降低HUVECs细胞的活力,明显上调黏附分子ICAM-1、VCAM-1和E-selectin的产生,增加其与单核细胞的黏附能力,可作为体外模型模拟炎症反应致内皮细胞炎症损伤；(2)PGE1浓度依赖性地降低损伤的HUVECs表面ICAM-1、VCAM-1和E-selectin的表达,降低单核-内皮细胞之间的黏附作用,从而阻止继发的炎症反应；(3)PGE1可明显抑制TNF-α诱导的NF-kB (p65)活化,这可能是PGE1抑制TNF-α诱导的内皮细胞损伤的原因之一；(4)PGE1抑制TNF-α诱导的细胞内ROS表达,这也可能是PGE1抑制TNF-α诱导的内皮细胞损伤的原因之一。由此可见,PGE1能够保护TNF-α损伤的HUVECs,这与其抑制TNF-α诱导的NF-kB (p65)活化和ROS产生。
综上所述,PGE1对氧化损伤和炎症损伤的HUVECs具有保护作用,这为PGE1治疗血管内皮损伤性疾病如动脉粥样硬化、心绞痛、心肌梗死、弥散性血管内凝血等提供药理学证据。
Endothelial dysfunction is critical pathogenic factor in the development of cardiovascular diseases such as atherosclerosis, hypercholesteremia and disseminated intravascular coagulation. Oxidative stress and inflammation play critical roles in endothelial dysfunction.
Prostaglandin E1 (PGE1), which is an important member of the prostaglandins family, is a product of arachidonic acid metabolism by cycloxygenase. PGE1 has vasodilator effects on the systemic and pulmonary circulation and cardio-protective effects during ischemia and reoxygenation. In addition, beneficial effects on angiogenesis, platelet aggregation, blood viscosity and fibrinolysis have been observed. Moreover, increasing attention has now been paid to the anti-oxidant activity, anti-inflammation activity and cytoprotective action of PGE1. PGE1 protected human retinal pigment epithelial cells against oxidative injury; prevented the production of ROS in the intestinal mucosa of methotrexate-treated rats; reduced circulating soluble adhesion molecules in peripheral vascular disease, peripheral arterial obstructive disease and hepatic ischemia/reperfusion injury. However, no direct evidence was provided about the protective effects of PGE1 on damaged vascular endothelium, which is an important contributor to the development of cardiovascular diseases.
This study, therefore, was conducted to examine the protective effect of PGE1 on human umbilical vein endothelial cells (HUVECs) injured by hydrogen peroxide (H2O2) or tumor necrosis factor-a (TNF-a), and explore its mechanisms.
We firstly examined the protective effect of PGE1 on HUVECs injured by H2O2, and find:(1) H2O2 (200uM) markedly increased cell permeability, damaged cellular antioxidant defenses and furthermore induced endothelial cell apoptosis. (2) PGE1 (0.25,0.50,1.00uM) dose-dependently increased cell viability and attenuated LDH release in H2O2-injuried HUVECs. (3) PGE1 (0.25,0.50,1.00uM) significantly reduced intracellular MDA, increased intracellular SOD and GSH-Pox activity, and reduced intracellular ROS in H2O2-injuried HUVECs. (4) PGE, (0.25,0.50, 1.00uM) significantly reduced apoptotic rate induced by H2O2 in a concentration-dependent manner. (5)PGE1 (0.25,0.50, 1.00uM) triggered NO release, eons protein and mRNA expression a dose-dependent manner in H2O2-injuried HUVEC. As stated above, we concluded that PGE1 significantly protected HUVECs from H2O2-induced cell damage, which was possibly mediated at least in part by a mechanism linked to the up-regulation of NO expression. Therefore, PGE1 inhibited vascular oxidative stress and further prevented the development of endothelial dysfunction.
Then we examined the protective effect of PGE1 on HUVECs injured by TNF-a, and find:(1) TNF-a (lOng/ml) significantly increased VCAM-1, ICAM-1 and E-selectin expression, increased THP-1 cell adhesion to HUVECs. (2) PGE] (0.25, 0.50,1.00uM) significantly reduced the increased protein and mRNA expression of VCAM-1, ICAM-1 and E-selectin in TNF-a-treated HUVECs. (3) PGE, inhibits THP-1 cell adhesion to TNF-a-treated HUVECs. (4) PGE, (0.25,0.50,1.00uM) significantly reduced the increased intracellular ROS induced by TNF-a in TNF-a-treated HUVECs. (4) PGE1 (0.25,0.5, 1.0uM) decreased the level of p65 in the nucleus and increased p65 in the cytoplasm in TNF-a-treated HUVECs. In other word, PGE1 inhibited nuclear translocation of p65 in TNF-a-treated HUVECs. In summary, the present data suggested that PGE1 suppressed TNF-a-induced vascular inflammation which was possibly mediated by inhibition of oxidative stress and NF-kB activation. Therefore, PGE1 inhibited vascular inflammation and further prevented the development of endothelial dysfunction.
In conclusion, PGE1 protected HUVECs from H2O2 or TNF-a induced injury, which shed light on the pharmacological basis for the clinical application of PGE1 for treatment of atherosclerosis and acute coronary syndrome, which are relevant to endothelial cell death.
本实验分别采用过氧化氢(H2O2)和肿瘤坏死因子-α(TNF-α)作为外源性自由基和炎症因子生成系统,模拟人脐静脉内皮细胞(HUVECs)的脂质过氧化损伤和炎症损伤过程,建立离体培养的HUVECs氧化损伤和炎症损伤模型,观察PGE1对氧化损伤和炎症损伤的HUVECs的保护作用,并探讨其可能机制,为其用于心、脑血管疾病的治疗提供药理学依据。
我们首先探讨PGE1对氧化损伤HUVECs的保护作用,发现：(1)H2O2(200μM)能显著降低HUVECs细胞的活力,诱导细胞凋亡,可作为体外模型模拟氧自由基致HUVECs细胞氧化应激损伤；(2)PGE1可显著增高H2O2损伤的HUVECs的细胞活力,抑制细胞内LDH释放；(3)PGE1能够启动HUVECs细胞内抗氧化防御机制,显著减少MDA的生成量,提高细胞内SOD的活性和GSH-Px的含量,清除细胞内的ROS；(4)PGE1对H2O2诱导的HUVECs细胞凋亡有明显抑制作用,可抑制凋亡细胞染色质形态学的变化,降低细胞凋亡率；(5)PGE1可提高H2O2损伤的HUVECs细胞的NO水平、eNOS mRNA和蛋白质的水平。由此可见,PGE1能够保护H2O2损伤的血管内皮细胞,NO途径在该过程中发挥重要作用。
我们接着探讨PGE1对炎症损伤HUVECs细胞的保护作用,发现：(1)TNF-a (10ng/ml)能显著降低HUVECs细胞的活力,明显上调黏附分子ICAM-1、VCAM-1和E-selectin的产生,增加其与单核细胞的黏附能力,可作为体外模型模拟炎症反应致内皮细胞炎症损伤；(2)PGE1浓度依赖性地降低损伤的HUVECs表面ICAM-1、VCAM-1和E-selectin的表达,降低单核-内皮细胞之间的黏附作用,从而阻止继发的炎症反应；(3)PGE1可明显抑制TNF-α诱导的NF-kB (p65)活化,这可能是PGE1抑制TNF-α诱导的内皮细胞损伤的原因之一；(4)PGE1抑制TNF-α诱导的细胞内ROS表达,这也可能是PGE1抑制TNF-α诱导的内皮细胞损伤的原因之一。由此可见,PGE1能够保护TNF-α损伤的HUVECs,这与其抑制TNF-α诱导的NF-kB (p65)活化和ROS产生。
综上所述,PGE1对氧化损伤和炎症损伤的HUVECs具有保护作用,这为PGE1治疗血管内皮损伤性疾病如动脉粥样硬化、心绞痛、心肌梗死、弥散性血管内凝血等提供药理学证据。
Endothelial dysfunction is critical pathogenic factor in the development of cardiovascular diseases such as atherosclerosis, hypercholesteremia and disseminated intravascular coagulation. Oxidative stress and inflammation play critical roles in endothelial dysfunction.
Prostaglandin E1 (PGE1), which is an important member of the prostaglandins family, is a product of arachidonic acid metabolism by cycloxygenase. PGE1 has vasodilator effects on the systemic and pulmonary circulation and cardio-protective effects during ischemia and reoxygenation. In addition, beneficial effects on angiogenesis, platelet aggregation, blood viscosity and fibrinolysis have been observed. Moreover, increasing attention has now been paid to the anti-oxidant activity, anti-inflammation activity and cytoprotective action of PGE1. PGE1 protected human retinal pigment epithelial cells against oxidative injury; prevented the production of ROS in the intestinal mucosa of methotrexate-treated rats; reduced circulating soluble adhesion molecules in peripheral vascular disease, peripheral arterial obstructive disease and hepatic ischemia/reperfusion injury. However, no direct evidence was provided about the protective effects of PGE1 on damaged vascular endothelium, which is an important contributor to the development of cardiovascular diseases.
This study, therefore, was conducted to examine the protective effect of PGE1 on human umbilical vein endothelial cells (HUVECs) injured by hydrogen peroxide (H2O2) or tumor necrosis factor-a (TNF-a), and explore its mechanisms.
We firstly examined the protective effect of PGE1 on HUVECs injured by H2O2, and find:(1) H2O2 (200uM) markedly increased cell permeability, damaged cellular antioxidant defenses and furthermore induced endothelial cell apoptosis. (2) PGE1 (0.25,0.50,1.00uM) dose-dependently increased cell viability and attenuated LDH release in H2O2-injuried HUVECs. (3) PGE1 (0.25,0.50,1.00uM) significantly reduced intracellular MDA, increased intracellular SOD and GSH-Pox activity, and reduced intracellular ROS in H2O2-injuried HUVECs. (4) PGE, (0.25,0.50, 1.00uM) significantly reduced apoptotic rate induced by H2O2 in a concentration-dependent manner. (5)PGE1 (0.25,0.50, 1.00uM) triggered NO release, eons protein and mRNA expression a dose-dependent manner in H2O2-injuried HUVEC. As stated above, we concluded that PGE1 significantly protected HUVECs from H2O2-induced cell damage, which was possibly mediated at least in part by a mechanism linked to the up-regulation of NO expression. Therefore, PGE1 inhibited vascular oxidative stress and further prevented the development of endothelial dysfunction.
Then we examined the protective effect of PGE1 on HUVECs injured by TNF-a, and find:(1) TNF-a (lOng/ml) significantly increased VCAM-1, ICAM-1 and E-selectin expression, increased THP-1 cell adhesion to HUVECs. (2) PGE] (0.25, 0.50,1.00uM) significantly reduced the increased protein and mRNA expression of VCAM-1, ICAM-1 and E-selectin in TNF-a-treated HUVECs. (3) PGE, inhibits THP-1 cell adhesion to TNF-a-treated HUVECs. (4) PGE, (0.25,0.50,1.00uM) significantly reduced the increased intracellular ROS induced by TNF-a in TNF-a-treated HUVECs. (4) PGE1 (0.25,0.5, 1.0uM) decreased the level of p65 in the nucleus and increased p65 in the cytoplasm in TNF-a-treated HUVECs. In other word, PGE1 inhibited nuclear translocation of p65 in TNF-a-treated HUVECs. In summary, the present data suggested that PGE1 suppressed TNF-a-induced vascular inflammation which was possibly mediated by inhibition of oxidative stress and NF-kB activation. Therefore, PGE1 inhibited vascular inflammation and further prevented the development of endothelial dysfunction.
In conclusion, PGE1 protected HUVECs from H2O2 or TNF-a induced injury, which shed light on the pharmacological basis for the clinical application of PGE1 for treatment of atherosclerosis and acute coronary syndrome, which are relevant to endothelial cell death.
引文
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[1]Vane J, Corin RE. Prostacyclin:A Vascular Mediator[J]. Eur J Vasc Endovasc Surg,2003,26(6):571-578.
[2]Kubis N, Levy BI. Angiogenic effect of prostaglandin I2 in relation with its effect on PPAR nuclear receptors[J]. JMol Cell Cardiol,2004,36(3):331-332.
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[12]Nakayama T, Soma M, Saito S, et al. Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction[J]. Am Heart J,2002,143(5):797-801.
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[1]Vane J, Corin RE. Prostacyclin:A Vascular Mediator[J]. Eur J Vasc Endovasc Surg,2003,26(6):571-578.
[2]Kubis N, Levy BI. Angiogenic effect of prostaglandin I2 in relation with its effect on PPAR nuclear receptors[J]. JMol Cell Cardiol,2004,36(3):331-332.
[3]Cipollone F, Cicolini G, Bucci M. Cyclooxygenase and prostaglandin synthases in atherosclerosis:Recent insights and future perspectives[J]. Pharmacol Ther, 2008,118(2):161-180.
[4]Chandrasekharan NV, Dai H, Roos KL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs:cloning, structure, and expression. Pharmacology.2002,99(21):13926-13931.
[5]Lee IY, Bae YD, Jeoung DI, et al. Prostacyclin production is not controlled by prostacyclin synthase but by cyclooxygenase-2 in a human follicular dendritic cell line[J]. Mol Immunol,2007,44(12):3168-3172.
[6]Bolego C, Buccellati C, Radaelli T, et al.eNOS, COX-2, and prostacyclin production are impaired in endothelial cells from diabetics[J]. Biochem Biophys Res Commun,2006,339(1):188-190.
[7]Kawka DW, Ouellet M, Hetu PO, et al. Double-label expression studies of prostacyclin synthase, thromboxane synthase and COX isoforms in normal aortic endothelium[J]. Biochim Biophys Acta,2007,1771(1):45-54.
[8]Wu KK, Liou JY. Cellular and molecular biology of prostacyclin synthase[J]. Biochem Biophys Res Commun,2005,338(9):45-52.
[9]Chiang CW, Yeh HC, Wang LH, et al. Crystal Structure of the Human Prostacyclin Synthase[J]. JMol Biol,2006,364(3):266-274.
[10]Hecker M, Ullrich V. On the mechanism of prostacyclin and thromboxane A2 biosynthesis[J]. J Biol Chem,1989,264:141-150.
[11]Nakayama T, Soma M, WatanabeY, et al. Splicing mutution of the Prostacyclin synthase gene in a family associated with hypertension[J]. Biochem Biophys Res Commun,2002,297(5):1135-1139.
[12]Nakayama T, Soma M, Saito S, et al. Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction[J]. Am Heart J,2002,143(5):797-801.
[13]Stitham J, Arehart EJ, Gleim SR, et al. Human prostacyclin receptor structure and function from naturally-occurring and synthetic mutations[J]. Prostag other Lipid Mediat,2007,82(1-4):95-108.
[14]Parkington HC, Coleman HA, Tare M. Prostacyclin and endothelium-dependent hyperpolarization[J]. Pharmacol Res,2004,49(6):509-514.
[15]金有豫,方云祥.前列腺素与白三烯的心血管药理[M]//陈修.心血管药理学.北京：人民卫生出版社,1997：80—100..
[16]Fetalvero KM, Shyu M, Nomikos AP, et al. The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway[J]. Am J Physiol Heart Circ Physiol,2006,290:H1337-H1346.
[17]Hasse A, Nilius SM, Schro K, et al. Long-term-desensitization of prostacyclin receptors is independent of the C-terminal tail[J]. Biochem Pharmacol,2003,65 (12) 1991-1995.
[18]O'Keeffe MB, Reid HM, Kinsella BT. Agonist-dependent internalization and trafficking of the human prostacyclin receptor:A direct role for Rab5a GTPase[J]. Biochim Biophys Acta,2008,1783(10):1914-1928.
[19]Wikstrom K, Reid HM, Hill M, et al. Recycling of the human prostacyclin receptor is regulated through a direct interaction with Rabl la GTPase[J]. Cell Signal, 2008,20(12):2332-2346.
[20]Spisni E, Griffoni C, Santi S, et al. Colocalization prostacyclin (PGI2) synthase-caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis[J]. Exp Cell Res,2001,266(1):31-43.
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