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Trimetazidine prevents macrophage‐mediated septic myocardial dysfunction via activation of the histone deacetylase sirtuin 1
Author(s) -
Chen Jing,
Lai Jinsheng,
Yang Lei,
Ruan Guoran,
Chaugai Sandip,
Ning Qin,
Chen Chen,
Wang Dao Wen
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13386
Subject(s) - proinflammatory cytokine , apoptosis , ampk , inflammation , medicine , macrophage , pharmacology , lipopolysaccharide , m2 macrophage , cancer research , immunology , chemistry , biology , protein kinase a , kinase , microbiology and biotechnology , biochemistry , in vitro
Background and Purpose Sepsis 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 Results Pretreatment 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.