小凹与小凹蛋白-1介导ox-LDL的摄取及跨内皮转运
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摘要
目的:研究氧化低密度脂蛋白跨内皮细胞转运的方式,试图揭示caveolae在胆固醇流出中的作用机制,并探讨caveolin-1与内皮细胞胆固醇摄取间存在的关系,寻找是否存在调节关系。
方法:用40μg/ml氧化低密度脂蛋白处理人脐静脉内皮细胞不同时间,分别用荧光和HPLC观察细胞内胆固醇含量变化;随后将已用氧化低密度脂蛋白荷脂的人脐静脉内皮细胞,撤去氧化低密度脂蛋白后再观察细胞内胆固醇含量变化。分别用三种caveolae阻滞剂carrageenan、filipin、nocodazole预处理人脐静脉内皮细胞1h后与40μg/ml氧化低密度脂蛋白孵育24h,用荧光倒置显微镜观察内皮细胞荷脂情况。将人脐静脉内皮细胞种植于transwell培养系统套皿上层,分别用三种阻滞剂预处理细胞1h后加入40μg/mlDiI荧光标记的氧化低密度脂蛋白于套皿上层孵育24h,取套皿下层液体用荧光分光光度计测荧光值。用FITC标记LOX-1后,用nocodazole阻滞cavolae运动,用荧光倒置显微镜观察LOX-1的运动情况。利用caveolin-1 SiRNA干扰技术沉默内皮细胞caveolin-1表达,同时检测内皮细胞在氧化低密度脂蛋白作用下NF-κB和LOX-1的表达情况。
结果:实验表明人脐静脉内皮细胞与氧化低密度脂蛋白孵育时,细胞荷脂呈时间依赖性增加,撤去氧化低密度脂蛋白后细胞内脂质逐渐减少。caveolae阻滞剂可明显阻滞内皮细胞对ox-LDL摄取,同时也可明显阻滞氧化低密度脂蛋白跨内皮细胞转运达49%, 72%和80%。免疫荧光结果表明LOX-1定位于caveolae中。SiRNA干扰实验表明沉默caveolin-1表达后,抑制了NF-κB核转位,同时LOX-1表达下调。
结论:
1.内皮细胞可摄取ox-LDL而荷脂,也可自发性流出所荷脂质。内皮细胞的ox-LDL受体-LOX-1-定位于caveolae中,caveolae在内皮细胞摄取ox-LDL的过程中起了一个运载体的作用,它同时也介导了ox-LDL的跨内皮细胞转运。
2. caveolin-1促使NF-κB核转位而活化,进一步上调LOX-1表达。
Objective: To explore the mechanisms involved in cholesterol transcytosis across endothelial cells and the effects of caveolae in this process,and determine the relation between caveolin-1 expression and cholesterol efflux in human umbilical vein endothelial cells
Method: Human umbilical vein Endothelial Cells(HUVEC) were incubated with ox-LDL(40μg/ml) for different times,and depleted ox-LDL from medium after lipid-loaded 24h for different times, we used fluorescence microscope and HPLC to determine the cholesterol content in HUVEC at varies times. We first incubated HUVEC with carrageenan, filipin, or nocodazole for 1h, and a 24h incubation was followed after addition of DiI-ox-LDL(40μg/ml), the DiI fluorescent was observed with fluorescent microscope after incubation. We grown HUVEC on a Transwell insert to obtain a tight monolayer and preincubated with carrageenan, filipin, or nocodazole in the apical reservoir for 1h, then incubated 24h after addition of DiI-ox-LDL(40μg/ml), at the end of incubation period, the fluorescence intensity of DiI-ox-LDL that transcytosised up to the bottom reservoir was determined by Fluorescence spectrophotometer. We preincubated HUVEC with or without nocodazole for 1h, and incubated for another 24h with ox-LDL, use Indirect Immunofluorescence to determine the location of LOX-1. We Knocked down cavoelin-1 by caveolin-1 siRNA in HUVEC, then determined the activation of NF-κB and expression of LOX-1.
Result: We incubated HUVEC with ox-LDL(40μg/ml) for different times and depleted ox-LDL from medium after lipid-loaded 24h for different times, we found that HUVEC intra-cellular cholesterol contents increased in a time-dependented manner, and decreased gradually after depletion of ox-LDL from medium. We first incubated HUVEC with carrageenan, filipin, or nocodazole for 1h, and a second 24h incubation was performed after addition of DiI-ox-LDL(40μg/ml), we found that carrageenan, filipin, and nocodazole could inhibit ox-LDL uptake by HUVEC significantly. We also found that, after pretreated with those drugs, the Fluorescence intensity of DiI-ox-LDL that transcytosised up to the bottom reservoir was decreased dramatically to 49%, 72% and 80% respectively, comparing to control group. When used Immunofluorescence to locate LOX-1,we found that LOX-1 focus in endochylema, but when preincubated with nocodazole, then incubated with ox-LDL, LOCX-1 still focus at plasma membrane. After silenced the cavoelin-1 in HUVEC, we found that NF-κB was inactivated and the expression of LOX-1 was decreased.
Conclusion
1. HUVEC could uptake lipid, also could release lipid by some mechanism inherent exist, and this process is spontaneous. LOX-1 associated with caveolae in HUVEC, it located with or within cavoelae. Caveolae could be a carrier for ox-LDL involved in uptake of ox-LDL by HUVEC. HUVEC was a post-house in ox-LDL translocation from blood plasma to subendothelium, and cavoelae played a important role in this process.
2. Ox-LDL up-regulated caveolin-1 expression, which triggered NF-κB activation and nuclear translocation, subsequent promoted LOX-1 gene transcription, at the end, LOX-1 expression up-regulated. In this pathway, caveolin-1 as a regulator play a important role in ox-LDL uptake by modulation of LOX-1’s expression in HUVEC.
方法:用40μg/ml氧化低密度脂蛋白处理人脐静脉内皮细胞不同时间,分别用荧光和HPLC观察细胞内胆固醇含量变化;随后将已用氧化低密度脂蛋白荷脂的人脐静脉内皮细胞,撤去氧化低密度脂蛋白后再观察细胞内胆固醇含量变化。分别用三种caveolae阻滞剂carrageenan、filipin、nocodazole预处理人脐静脉内皮细胞1h后与40μg/ml氧化低密度脂蛋白孵育24h,用荧光倒置显微镜观察内皮细胞荷脂情况。将人脐静脉内皮细胞种植于transwell培养系统套皿上层,分别用三种阻滞剂预处理细胞1h后加入40μg/mlDiI荧光标记的氧化低密度脂蛋白于套皿上层孵育24h,取套皿下层液体用荧光分光光度计测荧光值。用FITC标记LOX-1后,用nocodazole阻滞cavolae运动,用荧光倒置显微镜观察LOX-1的运动情况。利用caveolin-1 SiRNA干扰技术沉默内皮细胞caveolin-1表达,同时检测内皮细胞在氧化低密度脂蛋白作用下NF-κB和LOX-1的表达情况。
结果:实验表明人脐静脉内皮细胞与氧化低密度脂蛋白孵育时,细胞荷脂呈时间依赖性增加,撤去氧化低密度脂蛋白后细胞内脂质逐渐减少。caveolae阻滞剂可明显阻滞内皮细胞对ox-LDL摄取,同时也可明显阻滞氧化低密度脂蛋白跨内皮细胞转运达49%, 72%和80%。免疫荧光结果表明LOX-1定位于caveolae中。SiRNA干扰实验表明沉默caveolin-1表达后,抑制了NF-κB核转位,同时LOX-1表达下调。
结论:
1.内皮细胞可摄取ox-LDL而荷脂,也可自发性流出所荷脂质。内皮细胞的ox-LDL受体-LOX-1-定位于caveolae中,caveolae在内皮细胞摄取ox-LDL的过程中起了一个运载体的作用,它同时也介导了ox-LDL的跨内皮细胞转运。
2. caveolin-1促使NF-κB核转位而活化,进一步上调LOX-1表达。
Objective: To explore the mechanisms involved in cholesterol transcytosis across endothelial cells and the effects of caveolae in this process,and determine the relation between caveolin-1 expression and cholesterol efflux in human umbilical vein endothelial cells
Method: Human umbilical vein Endothelial Cells(HUVEC) were incubated with ox-LDL(40μg/ml) for different times,and depleted ox-LDL from medium after lipid-loaded 24h for different times, we used fluorescence microscope and HPLC to determine the cholesterol content in HUVEC at varies times. We first incubated HUVEC with carrageenan, filipin, or nocodazole for 1h, and a 24h incubation was followed after addition of DiI-ox-LDL(40μg/ml), the DiI fluorescent was observed with fluorescent microscope after incubation. We grown HUVEC on a Transwell insert to obtain a tight monolayer and preincubated with carrageenan, filipin, or nocodazole in the apical reservoir for 1h, then incubated 24h after addition of DiI-ox-LDL(40μg/ml), at the end of incubation period, the fluorescence intensity of DiI-ox-LDL that transcytosised up to the bottom reservoir was determined by Fluorescence spectrophotometer. We preincubated HUVEC with or without nocodazole for 1h, and incubated for another 24h with ox-LDL, use Indirect Immunofluorescence to determine the location of LOX-1. We Knocked down cavoelin-1 by caveolin-1 siRNA in HUVEC, then determined the activation of NF-κB and expression of LOX-1.
Result: We incubated HUVEC with ox-LDL(40μg/ml) for different times and depleted ox-LDL from medium after lipid-loaded 24h for different times, we found that HUVEC intra-cellular cholesterol contents increased in a time-dependented manner, and decreased gradually after depletion of ox-LDL from medium. We first incubated HUVEC with carrageenan, filipin, or nocodazole for 1h, and a second 24h incubation was performed after addition of DiI-ox-LDL(40μg/ml), we found that carrageenan, filipin, and nocodazole could inhibit ox-LDL uptake by HUVEC significantly. We also found that, after pretreated with those drugs, the Fluorescence intensity of DiI-ox-LDL that transcytosised up to the bottom reservoir was decreased dramatically to 49%, 72% and 80% respectively, comparing to control group. When used Immunofluorescence to locate LOX-1,we found that LOX-1 focus in endochylema, but when preincubated with nocodazole, then incubated with ox-LDL, LOCX-1 still focus at plasma membrane. After silenced the cavoelin-1 in HUVEC, we found that NF-κB was inactivated and the expression of LOX-1 was decreased.
Conclusion
1. HUVEC could uptake lipid, also could release lipid by some mechanism inherent exist, and this process is spontaneous. LOX-1 associated with caveolae in HUVEC, it located with or within cavoelae. Caveolae could be a carrier for ox-LDL involved in uptake of ox-LDL by HUVEC. HUVEC was a post-house in ox-LDL translocation from blood plasma to subendothelium, and cavoelae played a important role in this process.
2. Ox-LDL up-regulated caveolin-1 expression, which triggered NF-κB activation and nuclear translocation, subsequent promoted LOX-1 gene transcription, at the end, LOX-1 expression up-regulated. In this pathway, caveolin-1 as a regulator play a important role in ox-LDL uptake by modulation of LOX-1’s expression in HUVEC.
引文
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2 Murase T , Kume N , Korenaga R et al . Fluid shear stress tran2scriptionally induces lectin2like oxidized LDL receptor-1 in vascularendothelial cells. Ci rc Res , 1998 ;83 (3) :328～33
3 Jiawei Chen, Yong Liu et al . Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1163
4 Mingyi Chen, Tomoh Masaki et al .LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacology & Therapeutics 2002 ;95: 89– 100
5 Li DY, Zhang YC , Philips MI et al . Upregulation of endothelialreceptor for oxidized low2density lipoprotein receptor (LOX-1) incultured human coronary artery endothelial cells by angiotensin Ⅱ type 1 receptor activation. Ci rc Res , 1999 ;84 (9) :1043～9
6 M Chen, T Masaki, and T Sawamura LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther, Jul 2002; 95(1): 89-100
7 Jiawei Chen, Yong Liu et al . Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1163
8 Murase T , Kume N , Kataoka H et al . Identification of solubleforms of lectin2like oxidized LDL receptor-1. A rterioscler ThrombV asc Biol , 2000 ;20 (3) :715～205
9 Minami M , Kume N , Kataoka H et al . Transforming growth fac2tor2β1 increase the expression of lectin2like oxidized low2densitylipoprotein receptor-1. Biochem Biophys Res Commun , 2000 ;272
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13 Naohiko Kobayashi, Kazuyoshi Hara et al . Eplerenone Shows Renoprotective Effect by Reducing LOX-1–Mediated Adhesion Molecule, PKC -MAPK-p90RSK, and Rho-Kinase Pathway. Hypertension, Apr 2005; 45: 538 – 544
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17 Jawahar L. Mehta, Bo Hu, Jiawei Chen, and Dayuan Li Pioglitazone Inhibits LOX-1 Expression in Human Coronary Artery Endothelial Cells by Reducing Intracellular Superoxide Radical Generation. Arterioscler. Thromb. Vasc. Biol., Dec 2003; 23: 2203
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1 Sawamura T , Kume N , AoyamaT et al . An endothelial receptorfor oxidized low2density lipoprotein. Nat ure , 1997 ;386 (6620) :73～7
2 Murase T , Kume N , Korenaga R et al . Fluid shear stress tran2scriptionally induces lectin2like oxidized LDL receptor-1 in vascularendothelial cells. Ci rc Res , 1998 ;83 (3) :328～33
3 Jiawei Chen, Yong Liu et al . Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1163
4 Mingyi Chen, Tomoh Masaki et al .LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacology & Therapeutics 2002 ;95: 89– 100
5 Li DY, Zhang YC , Philips MI et al . Upregulation of endothelialreceptor for oxidized low2density lipoprotein receptor (LOX-1) incultured human coronary artery endothelial cells by angiotensin Ⅱ type 1 receptor activation. Ci rc Res , 1999 ;84 (9) :1043～9
6 M Chen, T Masaki, and T Sawamura LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther, Jul 2002; 95(1): 89-100
7 Jiawei Chen, Yong Liu et al . Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1163
8 Murase T , Kume N , Kataoka H et al . Identification of solubleforms of lectin2like oxidized LDL receptor-1. A rterioscler ThrombV asc Biol , 2000 ;20 (3) :715～205
9 Minami M , Kume N , Kataoka H et al . Transforming growth fac2tor2β1 increase the expression of lectin2like oxidized low2densitylipoprotein receptor-1. Biochem Biophys Res Commun , 2000 ;272
10 Morawietz H , Duerrschmidt N , Niemann B et al . Induction of theoxLDL receptor LOX-1 by endothelin-1 in human endothelial cells.Biochem Biophys Res Commun , 2001 ;284 (4) :961～5
11 Takatoshi Murase, Noriaki Kume et al . Identification of Soluble Forms of Lectin-Like Oxidized LDL Receptor-1. Arterioscler. Thromb. Vasc. Biol., Mar 2000; 20: 715.
12 Li DY, Jawahar L. Antisense to LOX-1 inhibits oxidized LDL2me2diated upregulation of monocyte chemoattractant protein-1 andmonocyte adhesion to human coronary artery endothelial cells. Circulation , 2000 ;101 (25) :2889～95
13 Naohiko Kobayashi, Kazuyoshi Hara et al . Eplerenone Shows Renoprotective Effect by Reducing LOX-1–Mediated Adhesion Molecule, PKC -MAPK-p90RSK, and Rho-Kinase Pathway. Hypertension, Apr 2005; 45: 538 – 544
14 Cominacini L , Pasini AF , Garbin U et al . Oxidized low densitylipoprotein (ox2LDL) binding to ox2LDL receptor-1 in endothelialcells induces the activation of NF2κB through an increased production of intracellular reactive oxygen species. J Biol Chem , 2000 ;275 (17) :12633～8
15 Cominacini L , Rigoni A , Pasini AF et al . The binding of . oxi2dized low density lipoprotein (ox2LDL) to ox2LDL receptor-1 re2duces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem ,2001 ;276 (17) :13750～5
16 B Hu, D Li, T Sawamura, and JL Mehta Oxidized LDL through LOX-1 modulates LDL-receptor expression in human coronary artery endothelial cells. Biochem Biophys ResCommun, Aug 2003; 307(4): 1008-12.
17 Jawahar L. Mehta, Bo Hu, Jiawei Chen, and Dayuan Li Pioglitazone Inhibits LOX-1 Expression in Human Coronary Artery Endothelial Cells by Reducing Intracellular Superoxide Radical Generation. Arterioscler. Thromb. Vasc. Biol., Dec 2003; 23: 2203
18 Dayuan Li and Jawahar L. Mehta Upregulation of Endothelial Receptor for Oxidized LDL (LOX-1) by Oxidized LDL and Implications in Apoptosis of Human Coronary Artery Endothelial Cells : Evidence From Use of Antisense LOX-1 mRNA and Chemical Inhibitors. Arterioscler. Thromb. Vasc. Biol., Apr 2000; 20: 1116.