Trimetazidine prevents macrophage-mediated septic myocardial dysfunction via activation of the histone deacetylase sirtuin 1.

background and purposeSepsis is a systemic inflammatory response accompanied by excessive production of inflammatory cytokines and cardiovascular dysfunction. Importantly, macrophage-derived pro-inflammatory agents play a key role in cardiovascular impairment in sepsis. Here we have investigated the effects of trimetazidine (TMZ) on pro-inflammatory responses of macrophages in endotoxin-induced myocardial dysfunction. EXPERIMENTAL APPROACH: Mice pretreated with TMZ were injected i.p. with LPS and cardiac function evaluated. Levels of macrophage infiltration, macrophage inflammatory response and cardiomyocyte apoptosis were measured using immunohistochemical staining, elisa, real-time RT-PCR, Western blot, TUNEL and flow cytometry assays. KEY

resultsPretreatment with TMZ prevented LPS-induced myocardial dysfunction and apoptosis. TMZ also lowered levels of pro-inflammatory cytokines in serum and cardiac tissue and myocardial macrophage infiltration. Bone marrow transplantation indicated that TMZ alleviated LPS-induced myocardial dysfunction via decreasing macrophage infiltration. TMZ reduced expression of pro-inflammatory cytokines in LPS-stimulated cardiac and peritoneal macrophages. Co-culture of TMZ-pretreated macrophages with cardiomyocytes and conditioned media from TMZ-pretreated macrophages both decreased LPS-induced cardiomyocyte apoptosis. The anti-apoptosis effects of TMZ resulted from decrease of pro-inflammatory cytokines, partly due to normalizing the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK)/Nrf2/haem oxygenase-1 and Sirt1/PPARα pathways in macrophages. Cytokine secretion was also regulated by ROS, which were attenuated by TMZ via activation of Sirt1, AMPK and PPARα. CONCLUSIONS AND IMPLICATIONS: TMZ protected against LPS-induced myocardial dysfunction and apoptosis, accompanied by inhibition of macrophage pro-inflammatory responses. Our studies suggest that TMZ might represent a novel therapeutic agent to prevent and treat sepsis-induced myocardial dysfunction.