The Clinical Implications Of Increased Coexpression Of Pregnancy Associated Plasma Protein-A And OX40 Ligand In Patients With Acute Coronary Syndromes

Acute coronary syndromes(ACS) are a group of clinical syndrome of unstable coronary atherosclerotic plaque due to coronary atheroma disruption of vulnerable atheromatous plaque or erosion of intima-triggering acute thrombosis or vascular spasm, inducing acute or subacute myocardial ischemia[including unstable angina(UA), ST-segment elevation myocardial infarction(STEMT) and non-ST-segment elevation myocardial infarction(NSTEMT)].Bodies of documents show that the occurrence of ACS is gradually increasing,and therefore it is emerging as a severe challenge in cardiovascular fields of the 21^st century.It's an important clinical role to early identify and diagnose and classify risk degree in ACS for making an effective therapeutic strategies and improving the prognosis of myocardial infarction.The mechanisms underlying ACS are a special organism response induced by multifactor and complex impacts.Lots of research evidences show that the key to the occurrence and the development of ACS is local inflammatory reaction in atheromatous plaque and immunity mediated and thrombosis.Of these factors,the stability of atheromatous plaque plays an important and determinant role during the ACS pathogenic processes.The interaction between different inflammatory factors and cytokines inner coronary atheroma augments the formation and the disruption of atheromatous plaque.Thereinto,it is becoming most interested in effects of the pregnancy associated plasma protein-A(PAPP—A) and OX40-OX40 ligand(OX40/OX40L) on ACS.PAPP-A is a member of the superfamily of zincbinding matrix metalloproteinase and interrelated with insulin-like growth factor(IGF) originally identified in the serum of pregnant women.The PAPP-A is abundantly expressed in vascular smooth muscle cells, extracelluar matrix,monocytes and vascular endothelial cells.And because the PAPP-A is a matrix metalloproteinase,it probably participates in inflammatory reactions of vascular wall.The levels of peripheral blood reflect the state of inflammatory reaction and the stability of atheromatous plaque.The proteolytic degradation of collagen and elastic fibers and structural disruption of fibrous cap induced by PAPP-A,results in the atheromatous plaque rupture and the thrombosis,which causes complete or incomplete blockade, leading to the occurrence of the ACS.However,OX40L is an important stimulated molecule in the processes of T cell-antigen presenting cell(T-APC) immune response and plays a key role in immune response.An important avenue in which OX40/OX40L binding may participates in activated T cell survival and proliferation via the inhibition of cell apoptosis,mediating the inflammatory reaction and impact on the development of atherosclerosis(AS).Up to date,a full of convincing evidences suggest that OX40L are predisposing genes of atherosclerosis carrying on the animal experiments.Recently, studies imply that the instability and the rupture of coronary atheromatous plaque are correlative with expression of PAPP-A and OX40L,which could be a serum marker during the ACS occurrence and development.However,the detail mechanisms underlying the processes are still not clear.Our recent studies also found that the expression of OX40L on platelets and T lymphocytes in patients with ACS,however monocytes are key cells participating in the formation,the development and the disruption of atheromatous plaque.Based on above,we carry on this study to investigate whether the expression of OX40L is abnormal and is correlative between the expression of PAPP-A and OX40L in patients with ACS.In our study,we measured the expression levels of serum PAPP-A and soluble OX40L (sOX40L) by enzyme-linked-immunosorbent assay(ELISA) and tested the expression levels of peripheral blood OX40L on monocytes by indirect-immunofluorescence flow cytometry in different treatment groups[including health control group,patients with ACS group,patients with stable angina(SA) group].All objects to be selected are treated with coronary angiography,and then we assesse the coronary artery via angiographic results.To analyze the correlation between serum PAPP-A and sOX40L expression levels and peripheral blood OX40L expression levels on monocytes compared with angiographic results.The results showed that:(1) the expression levels of serum PAPP-A and sOX40L were significantly higher in patients with ACS compared with healthy controls and with the group of patients with SA(p＜0.01);However,the difference between the SA group and control group was no significant(P＞0.05);(2) the expression levels of peripheral blood OX40 and OX40L on monocytes were significantly higher in patients with ACS compared with healthy controls and with the group of patients with SA(p＜0.01); However,the difference between SA group and control group was no significant(P＞0.05); (3) A positive correlation was observed between serum PAPP-A expression levels and sOX40L expression levels,and serum PAPP-A expression levels and OX40L expression levels on monocytes in patients with ACS(r₁=0.54,r₂=0.51,p＜0.0001);A no correlation was found between serum PAPP-A expression levels and sOX40L expression levels,and serum PAPP-A expression levels and OX40L expression levels on monocytes respectively in SA group and control group(r₁=0.012,r₂=0.004,p＞0.05);(4) Another positive correlation was found between serum CRP and serum PAPP-A expression levels,sOX40Lexpression levels,OX40L expression levels on monocytes respectively in patients with ACS(r1=0.5362,r2=0.4212,r3 =0.4527,p＜0.001),but no correlation was observed in SA(r1 =0.124,r2 =0.021,r3 =0.116,p＞0.05 ) and control group(r1 =0.109, r2 =0.198,r3 =0.084,p＞0.05,n =30);Both serum and membrane-bound OX40L,serum PAPP-A levels were not correlated with CTnI in patients with ACS.(r1=0.113,r2 =0.085,r3=0.093,p＞0.05).(5) The complex coronary stenoses in patients with ACS were significantly correlated with serum sOX40L expression levels as well as with serum PAPP-A expression levels,and with OX40L expression levels on monocytes respectively (r₁=0.56,r₂=0.55,r₃=0.4011,p＜0.001);However,the smooth coronary stenoses in patients with ACS were no significant correlation with serum sOX40L expression levels as well as with serum PAPP-A expression levels,and with OX40L expression levels on monocytes respectively(r₁=0.04,r₂=0.002,r₃=0.012,p＞0.05);What's more,the degree of coronary stenoses in patients with ACS were no significant correlation with the serum sOX40L expression levels as well as with serum PAPP-A expression levels,and with OX40L expression levels on monocytes respectively(r₁=0.030,r₂=0.023,r₃=0.032, p＞0.05).Our results demonstrated that the serum PAPP-A concentrations were significantly higher in patients with ACS compared with controls or patients with SA,which was consistent with previous reports.We found that the serum PAPP-A levels were significantly correlated with complex coronary stenoses in patients with ACS,but not with smooth stenoses and stenoses degree,indicating the PAPP-A levels were closely correlated with instability of atheromatous plaque.As we known,OX40L,belonging to tumor necrosis factor(TNF) family members,are mainly expressed on B lymphocytes, vascular endothelial cells and mononuclear macrophage activated T-APC,which isâ…¡type transmembrane glycoprotein.We also found that the expression levels of OX40L on monocytes and serum sOX40L were significantly higher in patients with ACS compared with healthy controls and with the group of patients with SA.In addition,our results also showed that a significant positive correlation was between serum PAPP-A expression levels and sOX40L expression levels,as well as OX40L expression levels on monocytes in patients with ACS.In order to investigate whether the inner-relevance were between the indexes above mentioned and the instable atheromatous plaque in patients with ACS,we analyzed angiographic results in all patients and found that three indexes(including the serum sOX40L expression levels,the serum PAPP-A expression levels,and the OX40L expression levels on monocytes) were positive correlation with the complex coronary stenoses,but not with the smooth stenoses and the stenoses degree if we looked on the parameter of complex coronary stenoses as a pathological characteristic of instable atheromatous plaque.Based on above our results,we can come to a conclusion:enhanced levels of serum PAPP-A and OX40L in patients with ACS may represent a marker of coronary disease activity,and the inflammatory reaction and the immunity activation may play an important role in pathogenic processes in patients with ACS.The positive correlation was found between serum CRP and serum PAPP-A expression levels,sOX40L expression levels,OX40L expression levels on monocytes respectively in patients with ACS,but no correlation was observed in SA and control group.The result indicated that there was an inner-relevance among the indexes above mentioned undergoing inflammatory reaction.Both serum and membrane-bound OX40L,serum PAPP-A levels were not correlated with CTnI in patients with ACS.The levels of PAPP-A and OX40L were not different between AMI and UA groups,but CTnI level was significantly higher in patients with AMI compared with UA.It showed that PAPP-A and OX40L are not the injury or infarction indexes of cardiac muscle.Therefore,the increased co-expression of PAPP-A and OX40L is more important clinical role to early identify and diagnose in ACS than CTnI.