炎症因子Daintain/AIF-1在动脉粥样硬化中的功能研究
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摘要
上世纪90年代以前,认为血浆中胆固醇和低密度脂蛋白浓度过高,是动脉粥样硬化的主要危险因素;认为动脉粥样硬化是一种非炎性病变。近20年来的研究发现,尽管生活方式改变和新药物的采用,可降低血浆胆固醇和低密度脂蛋白浓度,但心脑血管疾病仍然是美国、欧洲和亚洲部分地区造成死亡的主要疾病。近10年分子免疫学研究表明,动脉粥样硬化斑块处集中反映了一系列在细胞和分子水平上的炎症应答,动脉粥样硬化被鉴定为是一种炎症性疾病。
1994年,陈正望等人以猪小肠为原料,从中纯化并鉴定出一个多肽,命名为daintain。1996年,Utans等从大鼠心脏移植排斥反应所形成的动脉粥样硬化斑块组织中克隆出一个巨噬细胞因子allograft inflammatory factor-1 (AIF-1),由于二者的一级结构高度同源,故并称Daintain/AIF-1。作为一个由巨噬细胞分泌,与炎症、免疫相关的炎症因子,对Daintain/AIF-1在炎症、血管病变、肿瘤以及自身免疫性疾病等方面的影响有着越来越多的研究。本实验室前期研究表明,Daintain/AIF-1能够促进肿瘤增生、改变细胞周期、促进细胞增殖以及加剧1型糖尿病,由于这些都与炎症和免疫方面密切相关。此外,我们还发现Daintain/AIF-1在动脉粥样硬化组织中表达阳性,而在周围正常组织和正常人动脉血管组织中为弱阳性或阴性。这提示Daintain/AIF-1与动脉粥样硬化的发生、发展过程密切相关。然而,目前Daintain/AIF-1影响动脉粥样硬化进程的机理并不清楚。研究发现Daintain/AIF-1可以促进巨噬细胞、血管平滑肌细胞和动脉内皮细胞的增殖、迁移以及增强T淋巴细胞的分泌活动,表明它在巨噬细胞、血管平滑肌细胞和动脉内皮细胞等动脉粥样硬化组织中存在的细胞激活过程中发挥重要的作用。现在已经清楚,巨噬细胞向泡沫细胞的转化、动脉内皮损伤以及血管平滑肌增生在动脉粥样硬化的起始、发展直到斑块破裂过程中扮演重要角色。由此可预见,Daintain/AIF-1可能通过激活巨噬细胞、血管平滑肌细胞和动脉内皮细胞来作用于动脉粥样硬化的进程。因此为了进一步探讨Daintain/AIF-1在动脉粥样硬化发生中的作用及机理,本论文主要开展了以下工作:
1.通过免疫组织化学染色的方法,检测发现在动脉粥样硬化斑块处有大量的Daintain/AIF-1阳性区,而其周围的非病变区域中几乎不能检测到Daintain/AIF-1。
2.为进一步研究Daintain/AIF-1和动脉粥样硬化之间的关系,我们检测了病人血清中Daintain/AIF-1的含量。我们采用具有潜在动脉粥样硬化倾向的高血压病人血清来检测Daintain/AIF-1的含量,并发现与正常人相比,该类病人血清中其Daintain/AIF-1的含量较高,且与LDL-C的含量成正比关系,为Daintain/AIF-1研发成为一种新的动脉粥样硬化检测指标奠定了一定的基础。
3.为了更经济、方便地获得Daintain/AIF-1蛋白,我们采用基因工程方式,表达出了高纯度的Daintain/AIF-1。并基于其已经报道的部分活性做了检测,证明重组蛋白具有生物学功能活性;
4.寻找Daintain/AIF-1在小鼠胰腺和血管组织中的相互作用蛋白。此前,本实验室发现在体外Daintain/AIF-1能够与胱硫醚β合成酶相结合,通过原核表达的方法来获得胱硫醚β合成酶,用以研究Daintain/AIF-1对其酶活的影响;通过将重组的Daintain/AIF-1偶联在NTA-Ni介质上,与动脉血管组织裂解液结合洗脱后,发现一个新的结合蛋白——血红蛋白β1亚基,后续研究发现Daintain/AIF-1能够促使红细胞溶解和血红素的释放。
5.在体内,我们通过给小鼠尾静脉注射Daintain/AIF-1,研究其对小鼠体内与动脉粥样硬化相关的多项生化指标的影响。结果发现Daintain/AIF-1能使小鼠血清中的C反应蛋白、同型半胱氨酸、血糖浓度上升,降低超氧化物歧化酶的活性。
6.在体外,我们通过在培养基中添加Daintain/AIF-1的方式,探究Daintain/AIF-1对U937和HUVEC的功能特征的影响。结果显示,添加Daintain/AIF-1的实验组的增殖速率明显快于对照组。此外,我们还发现Daintain/AIF-1能够促进内皮细胞中的C-反应蛋白和一氧化氮合酶的基因表达。佛波醇-12-肉豆蔻酯-13-乙酯(PMA)趋化的U937巨噬细胞与ox-LDL共培养实验中发现,Daintain/AIF-1能够通过提高巨噬细胞表面的清道夫受体的表达,而增强巨噬细胞吞噬ox-LDL能力,从而促进巨噬细胞向泡沫细胞转化。
综上所述,Daintain/AIF-1在动脉粥样硬化形成和中后期的发展中发挥重要作用,有可能为动脉粥样硬化预防、诊断甚至治疗提供新的靶标。
Atherosclerosis is an inflammatory disease. Due to the high plasma cholesterol levels, particularly low-density lipoprotein (LDL) cholesterol, including the accumulation of lipids in the arterial wall, atherosclerosis is the major risk factor for atherosclerotic process has been considered by many groups. However, it is far more than that. While lifestyle changes and new ways to reduce the drug concentration in plasma cholesterol, cardiovascular disease is still the leading cause of death in the United States, Europe and most parts of Asia. In fact, atherosclerotic plaque reflects a series of highly responses focused on specific cellular and molecular level, the level of the inflammatory factors. Therefore, generally speaking, atherosclerosis is an inflammatory disease.
In 1994, Chen et al purified and identified a peptide from pig intestine, named daintain. In 1996, Utans et al cloned a new macrophage factor from the formation of atherosclerotic plaque tissue in cardiac allograft heart rejection, named allograft inflammatory factor-1 (AIF-1), daintain and AIF-1 shares similar two-level structure. So take tegather called it Daintain/AIF-1. As an inflammatory and immune-related inflammatory factor secretd by the macrophages, the researches of Daintain/AIF-1 in inflammation, vascular diseases, cancer and autoimmune diseases get more and more. Previous study in our laboratory showed that, Daintain/AIF-1 can promote tumor proliferation, changes in cell cycle, promotes cell proliferation and increases type 1 diabetes. All of these are closely associated with inflammation and immune response. In addition, we also found Daintain/AIF-1 in atherosclerotic tissues positive, and in the surrounding normal tissue and normal tissue in the arteries as a weak positive or negative. This suggests that Daintain/AIF-1 is closely related with the occurrence of atherosclerosis and the development process. However, the mechanism of Daintain/AIF-1 in atherosclerotic process is not clear. It has been found that Daintain/AIF-1 can promote macrophage, vascular smooth muscle cells and arterial endothelial cell proliferation, migration and enhance the secretory activity of T lymphocytes. Macrophages, vascular smooth muscle cells and arterial endothelial cells exist in atherosclerotic tissue inflect the processes of atherosclerosis, indicating that Daintain/AIF-1 plays an important role in atherosclerosis. It is now clear, macrophage transformation into foam cells, arterial endothelial dysfunction and vascular smooth muscle proliferation in atherosclerosis initiation, development through the process of plaque rupture plays an important role. Thus predictable, Daintain/AIF-1 possibly through activation of macrophages, vascular smooth muscle cells and arterial endothelial cells acts on the atherosclerotic process. Therefore, to further explore the Daintain/AIF-1 in the role and mechanism of artery atherosclerosis, we carried out the following work.
1. In the present study, we used immunohistochemical staining to detect the distribution of Daintain/AIF-1 in atherosclerotic plaques in the arteries and surrounding tissue. The results showed that atherosclerotic plaque has a large number of Daintain/AIF-1 positive phenomenon, and its surrounding normal tissue and vascular tissue of normal controls can almost not be detected Daintain/AIF-1.
2. To study Daintain/AIF-1 whether can be a new detection marker of atherosclerosis, we examined the content of Daintain/AIF-1 in the sera. Finding actually atherosclerosis patients is pre difficult, so we used the potential tendency of atherosclerosis in patients with hypertension to detect Daintain/AIF-1 serum levels, and found that compared with normal people, the Daintain/AIF-1 serum levels of these patients were much higher than the controls, and LDL-C levels were proportional with Daintain/AIF-1.
3. In order to obtain Daintain/AIF-1 protein more economically and conveniently, we designed prokaryotic expression system to express and purify high quality Daintain/AIF-1, and some of its bioactivity has been reported to do the validation.
4. Others study found that in vitro Daintain/AIF-1 can bind with cystathionineβ-synthase. And for the study of this combination, we employed the original expression to obtain the recombined cystathionineβ-synthase, to study the impact of Daintain/AIF-1 on the enzyme activity, but found no statistical value of its impact.
5. In vivo, we adopted the short and long-term approach to study the impact of Daintain/AIF-1 on biochemical changes of the mice injected with Daintain/AIF-1 or with not. The results showed that Daintain/AIF-1 could raise C-reactive protein, homocysteine, fibrinogen and blood sugar levels in the sera of mice, and impacted activity of SOD. These factors and the occurrence of atherosclerosis developments are closely linked.
6. For further study of the impact of Daintain/AIF-1 on monocytic U937 and HUVEC human umbilical vein endothelial cells proliferation and cytokine secretion in vitro, we added Daintain/AIF-1 to the medium, to explore the functional characteristics of Daintain/AIF-1 in U937 and HUVEC. The results show that adding Daintain/AIF-1 the proliferation rate of the experimental group was significantly faster than the control group. In addition, we also found Daintain/AIF-1 can promote C-reactive protein and nitric oxide synthase expression. Through phorbol -12- myristate acetate -13- acetate (PMA) derived U937 macrophages and ox-LDL co-culture experiments, we found that Daintain/AIF-1 presence through enhanced expression of scavenger receptor A to regulate macrophage - foam cell transformation rate.
In summary, Daintain/AIF-1 plays an important role in atherosclerotic plaque formation and development. Daintain/AIF-1 may be a new indicator on the atherosclerotic prediction, and may be a novel molecular target of atherosclerosis therapy.
1994年,陈正望等人以猪小肠为原料,从中纯化并鉴定出一个多肽,命名为daintain。1996年,Utans等从大鼠心脏移植排斥反应所形成的动脉粥样硬化斑块组织中克隆出一个巨噬细胞因子allograft inflammatory factor-1 (AIF-1),由于二者的一级结构高度同源,故并称Daintain/AIF-1。作为一个由巨噬细胞分泌,与炎症、免疫相关的炎症因子,对Daintain/AIF-1在炎症、血管病变、肿瘤以及自身免疫性疾病等方面的影响有着越来越多的研究。本实验室前期研究表明,Daintain/AIF-1能够促进肿瘤增生、改变细胞周期、促进细胞增殖以及加剧1型糖尿病,由于这些都与炎症和免疫方面密切相关。此外,我们还发现Daintain/AIF-1在动脉粥样硬化组织中表达阳性,而在周围正常组织和正常人动脉血管组织中为弱阳性或阴性。这提示Daintain/AIF-1与动脉粥样硬化的发生、发展过程密切相关。然而,目前Daintain/AIF-1影响动脉粥样硬化进程的机理并不清楚。研究发现Daintain/AIF-1可以促进巨噬细胞、血管平滑肌细胞和动脉内皮细胞的增殖、迁移以及增强T淋巴细胞的分泌活动,表明它在巨噬细胞、血管平滑肌细胞和动脉内皮细胞等动脉粥样硬化组织中存在的细胞激活过程中发挥重要的作用。现在已经清楚,巨噬细胞向泡沫细胞的转化、动脉内皮损伤以及血管平滑肌增生在动脉粥样硬化的起始、发展直到斑块破裂过程中扮演重要角色。由此可预见,Daintain/AIF-1可能通过激活巨噬细胞、血管平滑肌细胞和动脉内皮细胞来作用于动脉粥样硬化的进程。因此为了进一步探讨Daintain/AIF-1在动脉粥样硬化发生中的作用及机理,本论文主要开展了以下工作:
1.通过免疫组织化学染色的方法,检测发现在动脉粥样硬化斑块处有大量的Daintain/AIF-1阳性区,而其周围的非病变区域中几乎不能检测到Daintain/AIF-1。
2.为进一步研究Daintain/AIF-1和动脉粥样硬化之间的关系,我们检测了病人血清中Daintain/AIF-1的含量。我们采用具有潜在动脉粥样硬化倾向的高血压病人血清来检测Daintain/AIF-1的含量,并发现与正常人相比,该类病人血清中其Daintain/AIF-1的含量较高,且与LDL-C的含量成正比关系,为Daintain/AIF-1研发成为一种新的动脉粥样硬化检测指标奠定了一定的基础。
3.为了更经济、方便地获得Daintain/AIF-1蛋白,我们采用基因工程方式,表达出了高纯度的Daintain/AIF-1。并基于其已经报道的部分活性做了检测,证明重组蛋白具有生物学功能活性;
4.寻找Daintain/AIF-1在小鼠胰腺和血管组织中的相互作用蛋白。此前,本实验室发现在体外Daintain/AIF-1能够与胱硫醚β合成酶相结合,通过原核表达的方法来获得胱硫醚β合成酶,用以研究Daintain/AIF-1对其酶活的影响;通过将重组的Daintain/AIF-1偶联在NTA-Ni介质上,与动脉血管组织裂解液结合洗脱后,发现一个新的结合蛋白——血红蛋白β1亚基,后续研究发现Daintain/AIF-1能够促使红细胞溶解和血红素的释放。
5.在体内,我们通过给小鼠尾静脉注射Daintain/AIF-1,研究其对小鼠体内与动脉粥样硬化相关的多项生化指标的影响。结果发现Daintain/AIF-1能使小鼠血清中的C反应蛋白、同型半胱氨酸、血糖浓度上升,降低超氧化物歧化酶的活性。
6.在体外,我们通过在培养基中添加Daintain/AIF-1的方式,探究Daintain/AIF-1对U937和HUVEC的功能特征的影响。结果显示,添加Daintain/AIF-1的实验组的增殖速率明显快于对照组。此外,我们还发现Daintain/AIF-1能够促进内皮细胞中的C-反应蛋白和一氧化氮合酶的基因表达。佛波醇-12-肉豆蔻酯-13-乙酯(PMA)趋化的U937巨噬细胞与ox-LDL共培养实验中发现,Daintain/AIF-1能够通过提高巨噬细胞表面的清道夫受体的表达,而增强巨噬细胞吞噬ox-LDL能力,从而促进巨噬细胞向泡沫细胞转化。
综上所述,Daintain/AIF-1在动脉粥样硬化形成和中后期的发展中发挥重要作用,有可能为动脉粥样硬化预防、诊断甚至治疗提供新的靶标。
Atherosclerosis is an inflammatory disease. Due to the high plasma cholesterol levels, particularly low-density lipoprotein (LDL) cholesterol, including the accumulation of lipids in the arterial wall, atherosclerosis is the major risk factor for atherosclerotic process has been considered by many groups. However, it is far more than that. While lifestyle changes and new ways to reduce the drug concentration in plasma cholesterol, cardiovascular disease is still the leading cause of death in the United States, Europe and most parts of Asia. In fact, atherosclerotic plaque reflects a series of highly responses focused on specific cellular and molecular level, the level of the inflammatory factors. Therefore, generally speaking, atherosclerosis is an inflammatory disease.
In 1994, Chen et al purified and identified a peptide from pig intestine, named daintain. In 1996, Utans et al cloned a new macrophage factor from the formation of atherosclerotic plaque tissue in cardiac allograft heart rejection, named allograft inflammatory factor-1 (AIF-1), daintain and AIF-1 shares similar two-level structure. So take tegather called it Daintain/AIF-1. As an inflammatory and immune-related inflammatory factor secretd by the macrophages, the researches of Daintain/AIF-1 in inflammation, vascular diseases, cancer and autoimmune diseases get more and more. Previous study in our laboratory showed that, Daintain/AIF-1 can promote tumor proliferation, changes in cell cycle, promotes cell proliferation and increases type 1 diabetes. All of these are closely associated with inflammation and immune response. In addition, we also found Daintain/AIF-1 in atherosclerotic tissues positive, and in the surrounding normal tissue and normal tissue in the arteries as a weak positive or negative. This suggests that Daintain/AIF-1 is closely related with the occurrence of atherosclerosis and the development process. However, the mechanism of Daintain/AIF-1 in atherosclerotic process is not clear. It has been found that Daintain/AIF-1 can promote macrophage, vascular smooth muscle cells and arterial endothelial cell proliferation, migration and enhance the secretory activity of T lymphocytes. Macrophages, vascular smooth muscle cells and arterial endothelial cells exist in atherosclerotic tissue inflect the processes of atherosclerosis, indicating that Daintain/AIF-1 plays an important role in atherosclerosis. It is now clear, macrophage transformation into foam cells, arterial endothelial dysfunction and vascular smooth muscle proliferation in atherosclerosis initiation, development through the process of plaque rupture plays an important role. Thus predictable, Daintain/AIF-1 possibly through activation of macrophages, vascular smooth muscle cells and arterial endothelial cells acts on the atherosclerotic process. Therefore, to further explore the Daintain/AIF-1 in the role and mechanism of artery atherosclerosis, we carried out the following work.
1. In the present study, we used immunohistochemical staining to detect the distribution of Daintain/AIF-1 in atherosclerotic plaques in the arteries and surrounding tissue. The results showed that atherosclerotic plaque has a large number of Daintain/AIF-1 positive phenomenon, and its surrounding normal tissue and vascular tissue of normal controls can almost not be detected Daintain/AIF-1.
2. To study Daintain/AIF-1 whether can be a new detection marker of atherosclerosis, we examined the content of Daintain/AIF-1 in the sera. Finding actually atherosclerosis patients is pre difficult, so we used the potential tendency of atherosclerosis in patients with hypertension to detect Daintain/AIF-1 serum levels, and found that compared with normal people, the Daintain/AIF-1 serum levels of these patients were much higher than the controls, and LDL-C levels were proportional with Daintain/AIF-1.
3. In order to obtain Daintain/AIF-1 protein more economically and conveniently, we designed prokaryotic expression system to express and purify high quality Daintain/AIF-1, and some of its bioactivity has been reported to do the validation.
4. Others study found that in vitro Daintain/AIF-1 can bind with cystathionineβ-synthase. And for the study of this combination, we employed the original expression to obtain the recombined cystathionineβ-synthase, to study the impact of Daintain/AIF-1 on the enzyme activity, but found no statistical value of its impact.
5. In vivo, we adopted the short and long-term approach to study the impact of Daintain/AIF-1 on biochemical changes of the mice injected with Daintain/AIF-1 or with not. The results showed that Daintain/AIF-1 could raise C-reactive protein, homocysteine, fibrinogen and blood sugar levels in the sera of mice, and impacted activity of SOD. These factors and the occurrence of atherosclerosis developments are closely linked.
6. For further study of the impact of Daintain/AIF-1 on monocytic U937 and HUVEC human umbilical vein endothelial cells proliferation and cytokine secretion in vitro, we added Daintain/AIF-1 to the medium, to explore the functional characteristics of Daintain/AIF-1 in U937 and HUVEC. The results show that adding Daintain/AIF-1 the proliferation rate of the experimental group was significantly faster than the control group. In addition, we also found Daintain/AIF-1 can promote C-reactive protein and nitric oxide synthase expression. Through phorbol -12- myristate acetate -13- acetate (PMA) derived U937 macrophages and ox-LDL co-culture experiments, we found that Daintain/AIF-1 presence through enhanced expression of scavenger receptor A to regulate macrophage - foam cell transformation rate.
In summary, Daintain/AIF-1 plays an important role in atherosclerotic plaque formation and development. Daintain/AIF-1 may be a new indicator on the atherosclerotic prediction, and may be a novel molecular target of atherosclerosis therapy.
引文
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