Dataset Information

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

ABSTRACT:

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/PPAR? pathways in macrophages. Cytokine secretion was also regulated by ROS, which were attenuated by TMZ via activation of Sirt1, AMPK and PPAR?.

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.

SUBMITTER: Chen J

PROVIDER: S-EPMC4728416 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Chen Jing J Lai Jinsheng J Yang Lei L Ruan Guoran G Chaugai Sandip S Ning Qin Q Chen Chen C Wang Dao Wen DW

British journal of pharmacology 20151225 3

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Mice pretreated with TMZ were injected i ...[more]

PMID: 26566260

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Project description:BACKGROUND:Empagliflozin showed efficacy in controlling glycaemia, leading to reductions in HbA1c levels, weight loss and blood pressure, compared to standard treatment. Moreover, the EMPA-REG OUTCOME trial demonstrated a 14% reduction of major adverse cardiovascular events (MACE), a 38% reduction in cardiovascular (CV) death and a 35% reduction in the hospitalization rate for heart failure (HF). These beneficial effect on HF were apparently independent from glucose control. However, no mechanistic in vivo studies are available to explain these results, yet. We aimed to determine the effect of empagliflozin on left ventricular (LV) function in a mouse model of doxorubicin-induced cardiomyopathy (DOX-HF). METHODS:Male C57Bl/6 mice were randomly assigned to the following groups: controls (CTRL, n?=?7), doxorubicin (DOX, n?=?14), DOX plus empagliflozin (DOX?+?EMPA, n?=?14), or DOX plus furosemide (DOX?+?FURO group, n?=?7). DOX was injected intraperitoneally. LV function was evaluated at baseline and after 6 weeks of treatment using high-resolution echocardiography with 2D speckle tracking (Vevo 2100). Histological assessment was obtained using Haematoxylin and Eosin and Masson's Goldner staining. RESULTS:A significant decrease in both systolic and diastolic LV function was observed after 6 weeks of treatment with doxorubicin. EF dropped by 32% (p?=?0.002), while the LS was reduced by 42% (p?<?0.001) and the CS by 50% (p?<?0.001). However, LV function was significantly better in the DOX?+?EMPA group, both in terms of EF (61.30?±?11% vs. 49.24?±?8%, p?=?0.007), LS (- 17.52?±?3% vs. - 13.93?±?5%, p?=?0.04) and CS (- 25.75?±?6% vs. - 15.91?±?6%, p?<?0.001). Those results were not duplicated in the DOX?+?FURO group. Hearts from the DOX?+?EMPA group showed a 50% lower degree of myocardial fibrosis, compared to DOX mice (p?=?0.03). No significant differences were found between the DOX?+?FURO and the DOX group (p?=?0.103). CONCLUSION:Empagliflozin attenuates the cardiotoxic effects exerted by doxorubicin on LV function and remodelling in nondiabetic mice, independently of glycaemic control. These findings support the design of clinical studies to assess their relevance in a clinical setting.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

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