Study On The Relationship And Functions Of Fibrinogen And P-selectin In Atherosclerosis

Objective: Atherosclerosis is one of the most widespread conditions that alwaysthreaten human health and survival. The formation and development of atherosclerosisis always a chronic process, also its precise etiopathogenisis is not clear up to now. Ithas shown that platelet P-selectin (CD62P) plays an important role in atherosclerosis,some reported that fibrinogen (Fg) may take part in inflammation, thrombosis, andhemostasis via enhancement of platelet P-selectin expression, and play a vital role inatherosclerosis. In view of this, our study designs several trials to explore therelationship and functions of fibrinogen and P-selectin express in atherosclerosis, and toexamine the possible mechanism behind any effects of fibrinogen on atherosclerosis.Methods: We carry out the study in three parts, namely, the fibrinogen and P-selectinexpression in the formation of atherosclerosis; the changes of the index and P-selectinafter the input of fibrinogen induced in animal models of atherosclerosis; the changes offibrinogen and P-selectin in atherosclerosis following the drug intervention. Specifically,(1) Diet-induced and vitamin D2induced atherosclerosis Sprague Dawley (SD) ratswere adopted as experimental models. The blood from the common abdominal aorta ofthe rats was obtained to measure the biochemical characteristics and for the check offlow cytometry. Then the aortas were separated carefully, taken out, put into10%(w/v)neutral formalin for later use. Fg and P-selectin expression were detected by flowcytometry and immunohistochemistry.(2) Diet-induced and vitamin D2inducedatherosclerotic SD rats were adopted as experimental models. Fibrinogen wastransfused into part of these rats, and the degree of atherosclerotic lesion development was compared to control rats. Blood was obtained from the common abdominal aorta ofthe rats to measure biochemical characteristics and to perform ELISA assays.Pathological HE-stained sections were examined by light microscopy analysis, andimmunohistochemistry was performed for Fg or P-selectin on representative tissuesections.(3) Rabbits were randomly allocated to receive basal diet or a high fat diet(HFD) for4weeks. Four weeks later, animals in HFD group were divided into threegroups, and one rabbit received either rosuvastatin calcium (3mg/day),all-trans-retinoic acid (atRA)(5mg/kg/day) or the same volume of vehicle respectivelyfor next8weeks. Disease markers, including lipids, P-selectin, fibrinogen andinflammatory cytokines, were assayed at the end of the experiments using the ELISAmethod, flow cytometry, immunohistochemistry.Results:(1) SD rats were induced to atherosclerosis model by HFD and vitamin D2injected. It was discovered that the binding of fibrinogen and the expression ofP-selectin on the platelet increased in atherosclerosis model (Group H) than in thecontrol group (Group Z), and there were closely interrelated. Immunohistochemistryanalysis showed that high levels of fibrinogen and P-selectin expressed on the artery ofatherosclerosis rat model.(2) The fibrinogen-transfused, high-fat diet group developedatherosclerotic lesions more readily than the control group. Immunohistochemicalanalysis revealed that fibrinogen expression was higher in the endarterium offibrinogen-transfused, high-fat diet fed rats. Interestingly, P-selectin expression wascorrelated with fibrinogen expression.(3) In the HFD group there were markedincreases in plasma lipids and aortic plaque formation. P-selectin expression, fibrinogenbinding on platelets or deposition on the intima of the aorta also increased significantlyas did the levels of TNF-α, IL-6and fibrinogen in plasma. After8weeks of treatmentwith atRA, there was a significant decrease in plasma lipids and improvement in aorticlesions. AtRA also inhibited the expression of P-selectin and fibrinogen binding onplatelets and deposition on the intima of the aorta, as well as significant decreases in levels of inflammatory cytokines, TNF-α and IL-6in plasma.Conclusions: Fibrinogen and P-selectin were concerned with atherosclerosis. Fg caninteract with platelets, endothelial cells, smooth muscle cells and macrophages in orderto contribute to atherogenesis. It is also believed that Fg can interact with P-selectin inorder to contribute to the development of atherosclerosis, that is to say, high levels offibrinogen and P-selectin can be regarded as risk factors for markers of atherosclerosis.Fibrinogen actively promotes atherosclerotic lesion development, and one possiblemechanism for this is the ability of fibrinogen to enhance the expression of P-selectin,which can also facilitate atherosclerotic lesion development. Our data provide evidenceto show that atRA ameliorates HFD-induced AS in rabbits. This may be mediated byinhibition of platelet activation and inflammation. High levels of fibrinogen andP-selectin can be considered as risk factors for atherosclerosis, can also be used asmarkers of atherosclerosis.