YKL-40 Synergizes With TNF-α To Affect The Function Of HUVECs And The Related Mechanism

The cardiovascular and cerebrovascular diseases have the highest mortality in the world,these diseases which include cerebral infarction,acute myocardial infarct-ion and coronary heart diseases have been not only serious threats to human health,but also a huge burden to the society and family.Atherosclerosis is the important pathologic basis of many cardiovascular diseases,its pathogenesis which has exper-ienced the development process such as "lipid invasion theory","theory of smooth muscle cell proliferation","blood clots theory" and "theory of endothelial cell dysf-unction" is really complex.So far the blood vessel of the immune inflammatory re-sponse theory has been widely accepted by people.The innate and acquired immu-ne responses and inflammation caused by a variety of inflammatory substances have played a vital role in the process of the occurrence and development of atheroscl-erosis.Migration of inflammatory cells in the process of atherosclerosis,the import-ant steps and the key links of immune pathologly are now the hot spots in researc-hes of life science.YKL-40 is a secreted glycoprotein,as well as chitinases belonged to the 18th glycosyl hydrolase family.Since its peptide amino end contains three different ami-no acids:tyrosine,lysine,and leucine,and its relative molecular weight is 40 kDa,so it is named as YKL-40.YKL-40 is also known as cartilage glycoprotein-39,38-kDa heparin combinedglycoprotein and chitinase 3 like 1 protein.In recent years,researches have shown that it plays an important role in cell proliferation,differe-ntiation,inflammation and tissue remodeling.The over expression of YKL-40 is associated with the pathogenesis of a series of disease,it can activate tumor related signaling pathways and promote tumor angiogenesis,has a broad role in inflamma-tion,and can also be used as a fibroblast growth factor to activate some signaling pathways.However,its accurate biological function is still unclear.By immunohist-ochemical analysis researchers have found that YKL-40 is expressed in the smooth muscle cells of atherosclerotic plaques,in atherosclerosis plaques the mRNA of YKL-40 can also be detected highly expressed in macrophages,prompting that YKL-40 may play an important role in the process of atherosclerosis.Clinical studies have shown that the concentration of YKL-40 in serum of pati-ents with atherosclerosis is higher than that in serum of normal people.Since the vascular endothelial cells are physical barriers of blood and tissues,they widely re-gulate various physiological and pathological process which are involved in blood vessels.After the stimulation of proinflammatory factors,endothelial cells release adhesion molecules,which cause the adhesion and permeation of lymphocyte from the endothelial cells to the inflammatory focal under the intima.The intercellular adhesion molecule 1(ICAM-1)and the vascular cell adhesion molecule 1(VCAM-1)are usually expressed in endothelial cells,and they could recruit lymphocytes to the lining of the vessel walls,which is the initial phase of atherosis and attributed to atherosclerotic plaque formation.In this study,in order to investigate whether YKL-40 have inflammatory effects on vascular endothelial cells,which participate in the occurrence and development of atherosclerosis,we first used different concentrations of YKL-40 to stimulate human umbilical vein endothelial cells,we found that YKL-40 can’t promote human umbilical vein endothelial cells to express ICAM-1,VCAM-1.It demonstrated that YKL-40 individually had no significant proinflammatory effect on human umbilical-vein endothelial cells.But we found that YKL-40 and TNF-α combine to stimulate human umbilical vein endothelial cells,they can promote the high expression of ICAM-1,VCAM-1.It refered that YKL-40 can induce HUVECs to express ICAM-1 and VCAM-1 in a concentration and time dependent way with TNF-α,suggesting it may be a promoting factor of atherosclerosis.Nuclear factor-kappa B(NF-kappa B)participates in TNF-α induced expression of ICAM-1,VCAM-1.We also found that the NF-kappa B signaling molecules were involved in the regulation of the en-dothelial inflammation caused by YKL-40 and TNF-α.So YKL-40 could promote the activaty of NF-kappa B transcription factors,enhance the inflammatory reaction of endothelial cells induced by TNF-α,and we have laid the foundation for the atherosclerosis mechanism which is promoted by YKL-40.