Role And Mechanisms Of Monocyte Chemoattractant Protein-1(MCP-1) In Pathogenesis Of Viral Myocarditis

ROLE AND MECHANISMS OF MONOCYTE CHEMOATTRACTANT PROTEIN-1(MCP-1) IN PATHOGENESIS OF VIRAL MYOCARDITIS Viral myocarditis (VMC) is a common cardiovascular disease. In China, VMC cases have been increasing year after year. VMC has become one of the main causes of sudden unknown death events in teenagers. Moreover chronic VMC often results in dilated cardiomyopathy. These demonstrate that VMC has greatly threatened human health. However, up to now, the mechanism of VMC has been unclear, which leads to the lack of effective treatments of VMC. So it has importantly theoretic and practical significance to elucidate the mechanism of VMC.It is known that viral infection is an important pathogeny of VMC, and VMC caused by coxsackievirus group B type 3 (CVB3) infection accounts for more than fifty percent VMC cases. Previous studies showed that CVB3 could not only injury cardiac myocytes by Pro2A directly, but also induce indirect injury by non-specific and specific immune responses. It is well known that indirect immunological injury in VMC is associated with the infiltration of a great amount of inflammatory cells. The infiltration of inflammatory cells is one of characteristic pathological changes in VMC. However, no reports were found about how the infiltration of inflammatory cells was triggered and how inflammatory cells arrested in tissue to induce immunological injury. It would open a new window in understanding the pathogenesis of VMC to resolve these questions.Generally, the infiltration of inflammatory cells is a complex and multiple-stepped process involved in many cells and molecules. Induced by inflammatory signals and cell-adhesion molecules, various inflammatory cells accumulate in the site of infection. The process consists of rolling, adherence, extravasation and so on. It has been confirmed that chemokines (ChKs) can provide migrating signal, activate cells and initiate the trafficking of the inflammatory cells. Our previous study showed that after HBV infection, the expression level of hepatocyte house-keeping chemokine LARC changed, which could influence the infiltration of cytotoxic T lymphocytes (CTL). According to above, we hypothesized that CVB3 infection may change the expression of ChKs of myocardium, which provide migrating signal, activate the cells and initiate the trafficking of the inflammatory cells and then lead to VMC. Therefore, in this study we first established VMC models in vivo and in vitro. The expression of 19 characteristic ChKs in four ChKs subfamilies was detected by RT-PCR in order to screen the ChKs that may play an important role in VMC. Based on the results, we further studied the effects of CVB3 infection dose, infection time and CVB3 state on the expression of screened ChKs. Then by increasing expression level of the ChKs in myocardium or intervening with the ChKs, we studied the role of the ChKs in pathogenesis of VMC. Our study would provide new theoretic base and experimental evidence for prevention and therapy of VMC.PARTⅠ Expression profile of ChKs in myocardial tissue of VMC1. Expression profile of ChKs in myocardial tissue of VMC in vivoThe chemokine superfamily is divided into four subfamilies (CXC, CC, C, CX3C) based on the arrangement of their amino terminal cysteine residues. To date, over 50 chemokines and 19 chemokine receptors have been identified. In order to screen the ChKs that may play an important role in VMC, the expression of 19 ChKs was detected by RT-PCR in myocardial tissue of BALB/c mice that were inoculated intraperitoneally with CVB3. The results showed that 13 ChKs including MIP-2, MIG, IP-10, SDF-1 (CXC family), MIP-1β, MCP-1, MCP-2, MCP-3, MCP-5, MDC, RANTES (CC family), LTN (C family) and FKN (CX3C family) were detectable in the myocardial tissue of VMC mice, whereas only 10 ChKs including SDF-1, MIP-1β, MCP-1, MCP-2, MCP-3, MCP-5, MDC, RANTES, FKN, LTN were found in normal control. Six ChKs (BLC, BRAK, MIP-1α, Eot, LARC and ALP) were detected neither in VMC group nor in normal control. It indicated tha...