A Glucagon-like Peptide-1 Analog Exenatide Suppresses The Development Of Aortic Atherosclerotic Lesions Through Poly（ADP-ribose）Polymerase-1 Pathway In Diabetes ApoE^-/- Mice

Background:Diabetes is a common clinic disease which caused by many reasons, its morbidity is raised with the development of people’s living standard. In 2011, according to the International Diabetes Federation, there are about 282 million men and 317 million women global died of diabetes, and most of them died of cardiovascular complications. Therefore, the importance should be put on the treatment of cardiovascular complications. Today, there are three kinds of antidiabetic agents, they are oral antidiabetic agents, insulin and glucagon-like peptide-1(GLP-1) receptor agonists/DPP-Ⅳ inhibitors. GLP-1 is an important regulating hormone secreted by the intestinal cells L, it can regulate blood sugar level through a variety of mechanisms, which plays an important protective role in the whole systems and organs. Poly(ADP-ribose)polymerase-1(PARP-1) is a vital member of PARP super family, it is a kind of nucleoprotein. It is activated PARP-1 that plays an important role in the formation and development of vascular atherosclerosis. Induced nitric oxide synthase (iNOS) is a member of nitric oxide synthase, in common time, it is not expressed. However, when cells are pathological stimulated, they can produce many iNOS, which mediated multiple pathological processes. There has been some literatures confirmed that GLP-1 can protect islets microcirculation in endothelial cells through PARP-1/iNOS pathway. So we conclude that GLP-1 may delay the process of the vascular atherosclerosis of diabetes through PARP-1 pathway.Objective:1. To confirm if exenatide affects the formation and development of diabetes vascular atherosclerosis.2. To study the mechanisms how exenatide affects the formation and development of diabetes vascular atherosclerosis.Methods:2.1. Built the diabetes atherosclerosis modelThe male apoE-/- mice were randomly divided into three groups, they were all fed with high-fat diet. The last two groups were given peritoneal injection of streptozocin (STZ) to induce diabetes and infused with either placebo or exenatide for six weeks.2.2. Specimen CollectionAt the end of the treatment, animals were anaesthetized by pentobarbital sodium inhalation and decapitated. Leave their blood serum for blood glucose and serum lipids measure. Some of animals’hearts and whole aortas were removed and placed in-80℃. The other animals’hearts and whole aortas were put in 4% paraformaldehyde solution.2.3. The aortic pathological examination:To observe plaque area of the aortic root by HE staining, to observe the collagen content of plaque by sirus red, to observe the fat content of plaque by oil red, to observe the MOMA-2 and α-SMA content of plaque by immunohistochemical method, evaluate the stability of the plaques. Stability coefficient:(collagen area+smooth muscle cell area)/(oil red area+ macrophages area).2.4. Western Blot method:Detecting the expression of PARP-1 and iNOS in the aorta.2.5. Statistical analysis:All data presented as means ±SD. Statistical significance was declared atp<0.05.Results:Compared with the control group, the diabetes group exhibited higher serum total cholesterol, triglycerides, blood glucose, aortic atherosclerotic plaque area and lower plaque stability score and the expression of PARP-1 and iNOS increased. While compared with the diabetes group, the exenatide group exhibited lower serum total cholesterol, triglycerides, aortic atherosclerotic plaque area and higher plaque stability score,but the expression of PARP-1 and iNOS decreased.Conclusions:1. We can built diabetes model by peritoneal injection of STZ, and animals show typical diabetes symptoms.2. Exenatide can improve the symptoms of diabetes animals.3. Exenatide can suppresses the area of aortic atherosclerotic lesions and stable the aortic atherosclerotic plaques through PARP-1 pathway in diabetes apoE-/-mice.