@article { author = {Rameshrad, Maryam and Maleki-Dizaji, Nasrin and Soraya, Hamid and Seyed Toutounchi, Negisa and Barzegari, Abolfazl and Garjani, Alireza}, title = {Effect of A-769662, a direct AMPK activator, on Tlr-4 expression and activity in mice heart tissue}, journal = {Iranian Journal of Basic Medical Sciences}, volume = {19}, number = {12}, pages = {1308-1317}, year = {2016}, publisher = {Mashhad University of Medical Sciences}, issn = {2008-3866}, eissn = {2008-3874}, doi = {10.22038/ijbms.2016.7917}, abstract = {Objective(s): TLR-4 activates a number of inflammatory signaling pathways. Also, AMPK could be involved in anti-inflammatory signaling. The aim of this study was to identify whether stimulation of AMPK could inhibit LPS-induced Tlr-4 gene expression in mice hearts. Materials and methods: Heart AMPK activity and/or Tlr-4 expression was stimulated in different mice groups, using respectively IP injection of A-769662 (10 mg/kg) and LPS (2 mg/kg) or a combination of both agents. Moreover, compound-C (20 mg/kg), as an AMPK antagonist, was intraperitoneally co-administrated with both A-769662 and LPS in another group to investigate the role of AMPK activity on Tlr-4 regulation. After 8 hr, in addition to peripheral neutrophil cell count, myocardial p-AMPK, p-ACC as well as MyD88 protein contents and Tlr-4 expression was assessed by Western blotting and real-time qRT-PCR, respectively. TNF-α and IL-6 expression levels were also determined by ELISA. Results: LPS induced heart Tlr-4 expression (P<0.001) associating with an increase in the myocardial MyD88 protein content (P<0.001), elevation of heart TNF-α (P<0.01) and IL-6 (P<0.05) concentrations, and rise in the peripheral neutrophil cell count (P<0.001). Administration of A-769662 decreased LPS-induced Tlr-4 expression (P<0.01) and alleviated peripheral neutrophil cell count (P<0.01). The inhibitory effect of A-769662 on LPS-induced Tlr-4 expression was reversed by antagonizing AMPK with compound-C (P<0.001) which reduced p-AMPK (P<0.05) and p-ACC (P<0.01) myocardial protein contents in the LPS+A-769662 group. Conclusion: This study demonstrated that activation of AMPK, by A-769662 agent, could inhibit Tlr-4 expression and activity, suggesting a link between AMPK and Tlr-4 in heart tissue.}, keywords = {ACC,A-769662,AMPK,Compound-C Lipopolysaccharide,TLR-4}, url = {https://ijbms.mums.ac.ir/article_7917.html}, eprint = {https://ijbms.mums.ac.ir/article_7917_c6e102ce9fd836beabc0c3235560d57b.pdf} }