The Inflammatory Polypeptide Daintain/AIF-1, A Central Risk Factor For Atherosclerosis

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.