氧化高密度脂蛋白对内皮祖细胞功能影响及机制研究
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摘要
研究背景：高密度脂蛋白(high density lipoprotein, HDL)除了具有促进胆固醇逆转运、保护血管内皮、抗炎、抗氧化和抗血栓形成等多方面有益作用外,还有研究发现,HDL可以通过改善内皮祖细胞(endothelial progenitor cells, EPCs)数量及功能,从而有助于血管损伤后的修复。然而,在许多情况下HDL水平升高却并不介导保护作用,相反会导致心血管事件发生增加,造成这种现象的原因可能在于升高的HDL并不具备心血管保护作用,此时“高水平HDL”反而促进心血管事件的发生。目前已知,在糖尿病、冠心病等条件下,HDL易氧化修饰生成氧化高密度脂蛋白(ox-HDL)而发生功能逆转成为致病因素,但ox-HDL对EPCs功能的作用以及机制如何并不清楚。
研究目的：本研究旨在在前期有关EPCs研究的基础上,进一步观察ox-HDL对EPCs功能的影响并探讨其中的作用机制,为针对HDL功能改善的治疗以及减少EPCs功能损害奠定基础。
研究方法：首先采用密度梯度离心法从人外周血中分离、培养、鉴定得到EPCs。接下来,我们从三个方面研究ox-HDL对EPCs功能的影响及机制：(1)ox-HDL对EPCs相关表面受体基因表达的筛选：采用人基因表达芯片检测ox-HDL干预后EPCs基因表达的变化,并通过realtime PCR和Western Blot方法进一步验证差异基因；(2)ox-HDL对EPCs功能的影响：在第一部分研究结果的基础上,将EPCs分为对照组、HDL干预组(50ug/ml)、不同浓度ox-HDL干预组(10ug/ml、20ug/ml、50ug/ml)、CD36中和抗体阻断组和CD36中和抗体阻断加ox-HDL干预组,其中CD36中和抗体于干预前2小时提前加入,然后采用MTT法检测细胞增殖情况、ANNEXIN V/PI法检测细胞凋亡水平、ROS荧光法检测细胞内氧化应激水平、Transwell小室迁移实验检测EPCs迁移能力、Matrigel方法检测体外血管形成能力,ELISA方法检测细胞培养上清中的细胞因子(VEGF和TSP-1),此外,通过结扎离断右侧股动脉建立裸鼠单侧下肢缺血模型,模型建立后通过尾静脉输注给予干预后的EPCs,继续喂养2周后采用血管造影、免疫组织荧光的方法观察EPCs体内血管修复能力。(3) ox-HDL对EPCs功能影响的信号通路研究：干预分组的情况同第二部分,在干预结束后,收集细胞总蛋白和核蛋白,采用Western Blot方法检测MAPK通路(p38、JNK、ERK)相关蛋白的磷酸化水平,采用凝胶迁移实验(Electrophoretic Mobility Shift Assay, EMSA)方法检测NF-κB活性。
研究结果：(1)ox-HDL对EPCs相关表面受体基因表达的筛选：ox-HDL干预EPCs后,与细胞运输、转录调控、信号转导、应激反应、代谢、运动、分化、细胞周期、粘附等相关的基因表达均有变化,其中在与HDL或ox-HDL相关的受体中,ox-HDL干预后CD36表达显著增加,为未干预组2.3751倍,其余受体表达无显著变化。随后的realtime PCR和Western Blot的结果进一步验证了ox-HDL可以呈浓度依赖性促进CD36表达增加(P<0.05),而相对应的是HDL并无此作用。(2)ox-HDL对EPCs功能的影响：ox-HDL呈浓度依赖性促进EPCs凋亡,抑制其迁移、体外血管新生以及裸鼠肢体缺血后体内血管新生能力,促进EPCs内ROS水平(P<0.05),而对血管新生相关因子的影响主要表现在促进TSP-1表达及分泌(P<0.05),但对VEGF表达影响不显著,这些损害作用在预先给予CD36抗体处理后均有部分减轻。(3)ox-HDL对EPCs功能影响的信号通路研究：ox-HDL呈浓度依赖性促进p38 MAPK的磷酸化,而对MAPK通路的其他两方面ERK和JNK的磷酸化则无显著的影响,EMSA结果提示,ox-HDL呈浓度依赖性提高NF-κB的活性,且在预先给予CD36中和抗体处理后,ox-HDL对p38 MAPK和NF-κB的促进作用显著降低。
研究结论：我们的结果揭示了与HDL相反,ox-HDL具有损害EPCs功能的作用,该损害作用通过CD36受体途径介导,与p38 MAPK和NF-κB信号通路密切相关,这可能是缺血性疾病血管新生功能受损的重要机制之一。
Background:High density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on the vascular wall. Endothelial progenitor cells (EPCs) play an important role in neovascularization in chronic ischemic disease. EPCs number and functions are influenced by a lot of factors and EPCs number and functions are important predictors for cardiovascular events. Recent studies demonstrated that HDL could directly stimulate EPCs differentiation and enhance ischemia-induced angiogenesis. However, a number of reports have indicated that HDL is susceptible to oxidation and structural modifications in case of atherosclerosis and diabetes. Unlike HDL, oxidized HDL (oxHDL) lose the important protective functions and impacts neovascularization negatively. However, the effect of oxHDL on EPCs is still unclear.
Objective:The objective of this study is to investigate the effect of oxHDL on EPCs and the underlying mechanism.
Method:EPCs were isolated from human peripheral venous blood. Then the whole study were divided into three parts:(1) The human oligonucleotide microarray was applied to isolate and classify the differentially expressed genes between untreated EPCs and ox-HDL treated EPCs. Quantitative real-time PCR and Western blot were used to confirm the results from the microarray.(2) Cells were cultured and stimulated with different concentrations of oxHDL (0-50μg/mL), HDL (50μg/mL) in the absence and presence anti-CD36 neutralizing antibody. EPCs apoptosis and migration, angiogenesis and intracellular reactive oxygen species (ROS) levels were assayed. And the expression of thrombospondin-1(TSP-1) and vascular endothelial growth factor (VEGF) were measured by real-time PCR and ELISA. (3)The expression of mitogen-activated protein kinase (MAPK) family proteins (p38, ERK and JNK) and NF-κB were measured by by Western blot and EMSA.
Results:(1) The results of human oligonucleotide microarray showed oxHDL promoted the gene expression of CD36. Quantitative real-time PCR and Western blot results confirmed the results from the microarray. (2) oxHDL increased apoptosis and intracellular ROS levels and reduced the ability of migration and angiogenesis of EPCs in a dose dependent manner (all P<0.05). oxHDL also upregulated the expression of TSP-1 without affecting VEGF expression of EPCs. All oxHDL-mediated effects on EPCs could be significantly attenuated by pretreatment with anti-CD36 neutralizing antibody. (3) P38 MAPK and NF-κB were activated post oxHDL stimulation. All oxHDL-mediated effects on EPCs could be significantly attenuated by pretreatment with anti-CD36 neutralizing antibody.
Conclution:These findings suggest that oxHDL promote apoptosis and inhibit migration and angiogenesis function of EPCs. These effects were mainly mediated via scavenger receptor CD36 and P38/MAPK, NF-κB signaling pathways. The ability of oxHDL to negatively influence EPCs biology may represent a novel pathological mechanism for the development and progression of cardiovascular disease.
研究目的：本研究旨在在前期有关EPCs研究的基础上,进一步观察ox-HDL对EPCs功能的影响并探讨其中的作用机制,为针对HDL功能改善的治疗以及减少EPCs功能损害奠定基础。
研究方法：首先采用密度梯度离心法从人外周血中分离、培养、鉴定得到EPCs。接下来,我们从三个方面研究ox-HDL对EPCs功能的影响及机制：(1)ox-HDL对EPCs相关表面受体基因表达的筛选：采用人基因表达芯片检测ox-HDL干预后EPCs基因表达的变化,并通过realtime PCR和Western Blot方法进一步验证差异基因；(2)ox-HDL对EPCs功能的影响：在第一部分研究结果的基础上,将EPCs分为对照组、HDL干预组(50ug/ml)、不同浓度ox-HDL干预组(10ug/ml、20ug/ml、50ug/ml)、CD36中和抗体阻断组和CD36中和抗体阻断加ox-HDL干预组,其中CD36中和抗体于干预前2小时提前加入,然后采用MTT法检测细胞增殖情况、ANNEXIN V/PI法检测细胞凋亡水平、ROS荧光法检测细胞内氧化应激水平、Transwell小室迁移实验检测EPCs迁移能力、Matrigel方法检测体外血管形成能力,ELISA方法检测细胞培养上清中的细胞因子(VEGF和TSP-1),此外,通过结扎离断右侧股动脉建立裸鼠单侧下肢缺血模型,模型建立后通过尾静脉输注给予干预后的EPCs,继续喂养2周后采用血管造影、免疫组织荧光的方法观察EPCs体内血管修复能力。(3) ox-HDL对EPCs功能影响的信号通路研究：干预分组的情况同第二部分,在干预结束后,收集细胞总蛋白和核蛋白,采用Western Blot方法检测MAPK通路(p38、JNK、ERK)相关蛋白的磷酸化水平,采用凝胶迁移实验(Electrophoretic Mobility Shift Assay, EMSA)方法检测NF-κB活性。
研究结果：(1)ox-HDL对EPCs相关表面受体基因表达的筛选：ox-HDL干预EPCs后,与细胞运输、转录调控、信号转导、应激反应、代谢、运动、分化、细胞周期、粘附等相关的基因表达均有变化,其中在与HDL或ox-HDL相关的受体中,ox-HDL干预后CD36表达显著增加,为未干预组2.3751倍,其余受体表达无显著变化。随后的realtime PCR和Western Blot的结果进一步验证了ox-HDL可以呈浓度依赖性促进CD36表达增加(P<0.05),而相对应的是HDL并无此作用。(2)ox-HDL对EPCs功能的影响：ox-HDL呈浓度依赖性促进EPCs凋亡,抑制其迁移、体外血管新生以及裸鼠肢体缺血后体内血管新生能力,促进EPCs内ROS水平(P<0.05),而对血管新生相关因子的影响主要表现在促进TSP-1表达及分泌(P<0.05),但对VEGF表达影响不显著,这些损害作用在预先给予CD36抗体处理后均有部分减轻。(3)ox-HDL对EPCs功能影响的信号通路研究：ox-HDL呈浓度依赖性促进p38 MAPK的磷酸化,而对MAPK通路的其他两方面ERK和JNK的磷酸化则无显著的影响,EMSA结果提示,ox-HDL呈浓度依赖性提高NF-κB的活性,且在预先给予CD36中和抗体处理后,ox-HDL对p38 MAPK和NF-κB的促进作用显著降低。
研究结论：我们的结果揭示了与HDL相反,ox-HDL具有损害EPCs功能的作用,该损害作用通过CD36受体途径介导,与p38 MAPK和NF-κB信号通路密切相关,这可能是缺血性疾病血管新生功能受损的重要机制之一。
Background:High density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on the vascular wall. Endothelial progenitor cells (EPCs) play an important role in neovascularization in chronic ischemic disease. EPCs number and functions are influenced by a lot of factors and EPCs number and functions are important predictors for cardiovascular events. Recent studies demonstrated that HDL could directly stimulate EPCs differentiation and enhance ischemia-induced angiogenesis. However, a number of reports have indicated that HDL is susceptible to oxidation and structural modifications in case of atherosclerosis and diabetes. Unlike HDL, oxidized HDL (oxHDL) lose the important protective functions and impacts neovascularization negatively. However, the effect of oxHDL on EPCs is still unclear.
Objective:The objective of this study is to investigate the effect of oxHDL on EPCs and the underlying mechanism.
Method:EPCs were isolated from human peripheral venous blood. Then the whole study were divided into three parts:(1) The human oligonucleotide microarray was applied to isolate and classify the differentially expressed genes between untreated EPCs and ox-HDL treated EPCs. Quantitative real-time PCR and Western blot were used to confirm the results from the microarray.(2) Cells were cultured and stimulated with different concentrations of oxHDL (0-50μg/mL), HDL (50μg/mL) in the absence and presence anti-CD36 neutralizing antibody. EPCs apoptosis and migration, angiogenesis and intracellular reactive oxygen species (ROS) levels were assayed. And the expression of thrombospondin-1(TSP-1) and vascular endothelial growth factor (VEGF) were measured by real-time PCR and ELISA. (3)The expression of mitogen-activated protein kinase (MAPK) family proteins (p38, ERK and JNK) and NF-κB were measured by by Western blot and EMSA.
Results:(1) The results of human oligonucleotide microarray showed oxHDL promoted the gene expression of CD36. Quantitative real-time PCR and Western blot results confirmed the results from the microarray. (2) oxHDL increased apoptosis and intracellular ROS levels and reduced the ability of migration and angiogenesis of EPCs in a dose dependent manner (all P<0.05). oxHDL also upregulated the expression of TSP-1 without affecting VEGF expression of EPCs. All oxHDL-mediated effects on EPCs could be significantly attenuated by pretreatment with anti-CD36 neutralizing antibody. (3) P38 MAPK and NF-κB were activated post oxHDL stimulation. All oxHDL-mediated effects on EPCs could be significantly attenuated by pretreatment with anti-CD36 neutralizing antibody.
Conclution:These findings suggest that oxHDL promote apoptosis and inhibit migration and angiogenesis function of EPCs. These effects were mainly mediated via scavenger receptor CD36 and P38/MAPK, NF-κB signaling pathways. The ability of oxHDL to negatively influence EPCs biology may represent a novel pathological mechanism for the development and progression of cardiovascular disease.
引文
1. Krenning G, van Luyn MJ, Harmsen MC. Endothelial progenitor cell-based neovascularization: implications for therapy. Trends Mol Med. Apr 2009; 15(4):180-189.
2. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. NEng J Med. Sep 8 2005;353(10):999-1007.
3. Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair. Circulation. Jun 7 2005; 111 (22):2981-2987.
4. Florentin M, Liberopoulos EN, Wierzbicki AS, et al. Multiple actions of high-density lipoprotein. Curr Opin Cardiol. Jul 2008;23(4):370-378.
5. Petoumenos V, Nickenig G, Werner N. High density lipoprotein exerts vasculoprotection via endothelial progenitor cells. J Cell Mol Med. Aug 14 2008.
6. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. Nov 22 2007;357(21):2109-2122.
7. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. Mar 29 2007;356(13):1304-1316.
8. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. Apr 19 2007;356(16):1620-1630.
9. Sorrentino SA, Besler C, Rohrer L, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. Jan 5;121(1):110-122.
10. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol. Jun 10 2008;51(23):2199-2211.
11. Duffy D, Rader DJ. Update on strategies to increase HDL quantity and function. Nat Rev Cardiol. Jul 2009;6(7):455-463.
12. Undurti A, Huang Y, Lupica JA, et al. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J Biol Chem. Nov 6 2009;284(45):30825-30835.
13. Nakajima T, Origuchi N, Matsunaga T, et al. Localization of oxidized HDL in atheromatous plaques and oxidized HDL binding sites on human aortic endothelial cells. Ann Clin Biochem. Mar 2000;37 (Pt 2):179-186.
14. Feng H, Li XA. Dysfunctional high-density lipoprotein. Curr Opin Endocrinol Diabetes Obes. Apr 2009;16(2):156-162.
1. Krenning G, van Luyn MJ, Harmsen MC. Endothelial progenitor cell-based neovascularization: implications for therapy. Trends Mol Med. Apr 2009;15(4):180-189.
2. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. NEngl J Med. Sep 8 2005;353(10):999-1007.
3. Florentin M, Liberopoulos EN, Wierzbicki AS, et al. Multiple actions of high-density lipoprotein. Curr Opin Cardiol. Jul 2008;23(4):370-378.
4. Petoumenos V, Nickenig G, Werner N. High density lipoprotein exerts vasculoprotection via endothelial progenitor cells. J Cell Mol Med. Aug 14 2008.
5. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. Nov 22 2007;357(21):2109-2122.
6. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. NEngl J Med. Mar 29 2007;356(13):1304-1316.
7. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. NEngl J Med. Apr 19 2007;356(16):1620-1630.
8. Sorrentino SA, Besler C, Rohrer L, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. Jan 5;121(1):110-122.
9. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol. Jun 10 2008;51(23):2199-2211.
10. Duffy D, Rader DJ. Update on strategies to increase HDL quantity and function. Nat Rev Cardiol. Jul 2009;6(7):455-463.
11. Undurti A, Huang Y, Lupica JA, et al. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J Biol Chem. Nov 6 2009;284(45):30825-30835.
12. Nakajima T, Origuchi N, Matsunaga T, et al. Localization of oxidized HDL in atheromatous plaques and oxidized HDL binding sites on human aortic endothelial cells. Ann Clin Biochem. Mar 2000;37 (Pt 2):179-186.
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1. Krenning G, van Luyn MJ, Harmsen MC. Endothelial progenitor cell-based neovascularization: implications for therapy. Trends Mol Med. Apr 2009; 15(4):180-189.
2. Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type Ⅱ diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. Nov 26 2002;106(22):2781-2786.
3. Petoumenos V, Nickenig G, Werner N. High density lipoprotein exerts vasculoprotection via endothelial progenitor cells. J Cell Mol Med. Aug 14 2008.
4. Sorrentino SA, Besler C, Rohrer L, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. Jan 5;121(1):110-122.
5. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol. Jun 10 2008;51(23):2199-2211.
6. Duffy D, Rader DJ. Update on strategies to increase HDL quantity and function. Nat Rev Cardiol. Jul 2009;6(7):455-463.
7. Undurti A, Huang Y, Lupica JA, et al. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J Biol Chem. Nov 6 2009;284(45):30825-30835.
8. Nakajima T, Origuchi N, Matsunaga T, et al. Localization of oxidized HDL in atheromatous plaques and oxidized HDL binding sites on human aortic endothelial cells. Ann Clin Biochem. Mar 2000;37 (Pt 2):179-186.
9. Feng H, Li XA. Dysfunctional high-density lipoprotein. Curr Opin Endocrinol Diabetes Obes. Apr 2009;16(2):156-162.
10. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. NEngl J Med. Sep 8 2005;353(10):999-1007.
11. Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair. Circulation. Jun 7 2005;11l(22):2981-2987.
12. Ma FX, Zhou B, Chen Z, et al. Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase. J Lipid Res. Jun 2006;47(6):1227-1237.
13. Di Santo S, Diehm N, Ortmann J, et al. Oxidized low density lipoprotein impairs endothelial progenitor cell function by downregulation of E-selectin and integrin alpha(v)beta5. Biochem Biophys Res Commun. Sep 5 2008;373(4):528-532.
14. Florentin M, Liberopoulos EN, Wierzbicki AS, et al. Multiple actions of high-density lipoprotein. Curr Opin Cardiol. Jul 2008;23(4):370-378.
15. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. NEngl J Med. Nov 22 2007;357(21):2109-2122.
16. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. Mar 29 2007;356(13):1304-1316.
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