effect of a-769662, a direct ampk activator, on tlr-4 expression and activity in mice heart tissue

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.