Valsartan independent of AT 1 receptor inhibits tissue factor, TLR ‐2 and ‐4 expression by regulation of Egr‐1 through activation of AMPK in diabetic conditions

Patients suffering from diabetes mellitus ( DM ) are at a severe risk of atherothrombosis. Early growth response (Egr)‐1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor ( AT 1 R) can reduce tissue factor ( TF ) and toll‐like receptor ( TLR )‐2 and ‐4 by regulating Egr‐1 in THP ‐1 cells and aorta in streptozotocin‐induced diabetic mice. High glucose ( HG , 15 mM) increased expressions of Egr‐1, TF , TLR ‐2 and ‐4 which were significantly reduced by valsartan. HG increased Egr‐1 expression by activation of PKC and ERK 1/2 in THP ‐1 cells. Valsartan increased AMPK phosphorylation in a concentration and time‐dependent manner via activation of LKB 1. Valsartan inhibited Egr‐1 without activation of PKC or ERK 1/2. The reduced expression of Egr‐1 by valsartan was reversed by either silencing Egr‐1, or compound C, or DN ‐ AMPK ‐transfected cells. Valsartan inhibited binding of NF ‐κB and Egr‐1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine ( TNF ‐α, IL ‐6 and IL ‐1β) production and NF ‐κB activity in HG ‐activated THP ‐1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT 1 R in THP ‐1 cells or CHO cells, which were devoid of AT 1 R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr‐1, TLR ‐2, ‐4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin‐induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK /Egr‐1 regulation.