The Anti-atherosclerosis Study On The Role And Mechanism Of Rosiglitazone

Backgroud:Background and purposeAtherosclerotic cardiovascular and cerebrovascular disease are serious threat to human health, the highest levels of mortality in developed countries, the incidence in China is also increasing year by year, and is one of the hot focus current study. Insulin resistance (IR) is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. IR and compensatory hyperinsulinemia lead to group disorder syndrome such as obesity, high blood pressure, high cholesterol, high blood sugar, high uric acid metabolism, and is closely related to cardiovascular and cerebrovascular disease. The present study show that in atherosclerosis and the occurrence and development of insulin resistance, the inflammatory response plays an important role, and linked atherosclerosis and insulin resistance organically. Insulin sensitizer rosiglitazone (RSG) is a peroxisome proliferator-activated receptor stimulator, currently mainly used in the treatment of type 2 diabetes, to improve insulin resistance, correct high blood glucose and high insulin disease, delay the occurrence of vascular complications. We look forward to it play a role in atherosclerosis prevention and treatment. The purpose of this study is to reseach the effect of rosiglitazone in rabbits blood lipid and aortic lipid deposition area, light microscopy, electron microscopy and aortic eNOS NF-κB, and to explore its mechanism.Methods:1,37 healthy male rabbits were randomly divided into 3 groups: control group, arteriosclerosis group and rosiglitazone group, high fat diet plus bovine serum stimulate prepared rabbit model of atherosclerosis hardening in arteriosclerosis group. Rosiglitazone group will also be mixed with rosiglitazone in the first delivery of feed.2,Rabbits were killed at the end of 14th week, measuring serum total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), fasting insulin (FINS). Calculated insulin resistance index HOMA-IR.3,Observed of specimens for atherosclerosis formation, the systemetic measure plaque area, vessel area, calculate percentage of plaque area in the total area.4,Observed of fibrous cap thickness, lipid core size, histological changes of the internal plaque of aortic atherosclerotic lesions.5,Observe changes in endothelial of aortic atherosclerotic plaque cells using electron microscopy.6,Aortic specimens, eNOS, NF-κB expression were observed and semi-quantitative analysised by using immunohistochemical SP method.Result:1,Successfully established rabbit atherosclerotic model.2,In rosiglitazone group, TC, TG, LDL-C and FBG has been reduced than in atherosclerosis group, but not significant difference. In Rosiglitazone group HDL-C atherosclerosis was significantly higher (P<0.01) and FINS, HOMA-IR significantly decreased (P<0.05).3,In blank control group ,the large specimens can be seen a very small amount of scattered the needle-like-size red spots; in atherosclerosis group, a large area continuous chip massive red plaque lesions were found, the average percentage of arterial vascular lipid deposit area is 74.7±11.9% of the total vascular area; in rosiglitazone group, dark red flake form atherosclerotic lesions to the proximal aorta were found, especially aortic arch ,discrete and scattered, and The average area of arterial lipid is 29.9±11.6% of total area of vascular, the average arterial lipid deposit area is 59.92% lower than the model group, (P <0.01).4,The results of light microscopy: in blank control group, the three-membrane structure of aortic membrane can be seen ,inner ,middle and outer membrane. Inner menbrane is composed by endothelial cells and loose connective tissue under the endothelium, intimal smooth, without loss of endothelial cells, subendothelial lipid-free. Middle menbrane is formed by dozens of layers of membrane elastic fiber ring and smooth muscle cells. outer membrane Constituted by the thin of connective tissue. Aortic atherosclerosis group is the endometrial lesions can be seen a large number of subendothelial accumulation of foam cells, accompanied by a small amount of fibrous tissue to form a convex plaque into the lumen of the large, circular patch of an area of about 1/4-1/3 of artery. In Rosiglitazone group, the three-membrane structure of aortic membrane can be seen, inner, middle and outer membrane. In middle and outer membrane structure no obvious abnormalities can be seen. In inner menbrane a small amount of foam cells accumulate, forming convex into the lumen of the focal spot block, but significantly less than the area of atherosclerotic plaque group.5,The results of electron microscopy: in blank control group, aortic endothelial cells are flat and complete, adjacent endothelial cells connected closely, nuclear is integrity, internal elastic membrane straight and uniform, no obvious lipid vacuoles and collagen fiber hyperplasia.in Atherosclerosis Group aortic endothelial cells can be seen a large number of lipid deposition, smooth muscle cells contain more lipid; internal elastic membrane thinned uneven, or even missing in some places; the space between endothelial cells and internal elastic membrane become big, collagen fibers hyperplasia, deposition of collagen fibers between cells with disorder, a large number of subendothelial lipid was found. In Rosiglitazone group, integrity of aortic endothelial cells is good, the nuclear oval-shaped, deposition of collagen fibers and a small amount of lipid vacuoles can be seen under the endothelial; carotid artery endothelial cell integrity, oval-shaped nuclear ,chromatin in central, no subendothelial lipid deposit.6,The results of immunohistochemistry: eNOS aortic images show staining cells is vascular endothelial cells, at low times and high time field of staining cells have show the lower proportion, staining intensity shallow, brown. In atherosclerosis group bubble cell cytoplasmic weak positive staining, positive for vascular endothelial cells. in rosiglitazone group, endothelial cells in the proportion and intensity of staining were significantly increased .focal foam cells also increased, and showed strong positive staining brown particles. In blank control group NF-κB was negative. Atherosclerosis group foam cells were strongly positive staining, endometrial vascular endothelial cells strongly positive. By rosiglitazone treatment of foam cells showed cytoplasmic staining of moderate intensity. Semi-quantitative image analysis showed that in rosiglitazone group eNOS was significantly lower (P<0.01) and NF-κB was significantly higher (P<0.01) than atherosclerosis group.Conclusion:1,Rosiglitazone can increase eNOS expression and improve endothelial function, prevent and treat atherosclerosis.2,Rosiglitazone can regulate inflammation by regulating NF-κB and then prevent and treat atherosclerosis.