P6306Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells

Abstract

Abstract Background In clinical situation, patients with myocardial infarction (MI) usually suffered from hyperlipidemia, hypertension, renal dysfunction or diabetes as well and the interaction of those risk factors may affect the effectiveness of ACEI. Dendritic cell (DC) is a potent central immunoregulator that orchestrates various types of inflammatory cells in innate and adoptive immunity. The role of DCs in the inflammation of cardiovascular disease is a hotspot of international research. Purpose To investigate the improvement of cardiac remodeling and inflammatory immune response after MI via ACEI regulating DCs and explore that whether the protective effect of ACEI is under the circumstance of hyperlipidemia. Methods In vivo, MI mice models were created via coronary artery ligation. We detected the survival and left ventricular function on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were obtained and assessed for Ang2 concentration, inflammatory cytokines and DCs expression via immunohistochemistry, ELISA, flow cytometry and western blot. In vitro, we treated DCs with ox-LDL+AngIIfor 48 hours simulating the internal environment of MI in ApoE−/− mice to explore the mechanism involved in the DCs maturation and inflammation. Results Under the circumstance of hyperlipidemia, the cardioprotective effect of ACEI is attenuated through regulating DCs maturation and inflammation after MI, including survival rate (Figure 1) and left ventricular function. The number of DCs in cardiac tissue were increased in MI mice with hyperlipidemia (Figure 2), when compared with the WT group. The expression of the maturity phenotype related molecules, such as CD83, on the DCs in spleen were also increased in the ApoE−/− mice. Then, the expressions of inflammatory cytokines, such as IL-6 and TNF-α. In vitro, it was found that the immune maturation and inflammation of DCs could be further induced by ox-LDL on the basis of AngIItreatment, as indicated by the upregulation of CD83 and CD86, the expressions of cytokines and chemokines. Furthermore, ox-LDL could activate the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) signaling pathway, promoting the phosphorylation of interleukin-1 receptor associated kinase (IRAK)-4 and the nuclear transferring of nuclear factor-kappaB (NF-κB). Conclusion We proved ACEI reduces the recruitment of DCs to the infarct, leading to a higher survival rate and improved function and remodeling through decreased inflammation resulting from immune response after MI. However, this effect was inhibited under the circumstance of hyperlipidemia. TLR4-MyD88 signaling pathway might be the possible molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox-LDL on the basis of AngII. Acknowledgement/Funding the Youth fund of the National Natural Science Foundation of China, Grant 81600280