Abstract
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 (AT1R) 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 ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. 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 AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. 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.
Highlights
Tissue factor (TF) is an important protein, as the key trigger of the coagulation cascade, and as a mediator in the pathogenesis of cardiovascular disorders
By acting as a master transcription factor, Early growth response (Egr)-1, a zinc finger nuclear protein, regulates a set of genes implicated in the pathogenesis of atherosclerosis, with subsequent thrombosis and restenosis [11, 12]
It should be noted that phosphorylation of PKC by HG was not affected by PD98059 (ERK inhibitor), but phosphorylation of ERK1/2 by HG was significantly reduced by G€o6976, indicating that ERK1/2 MAPK is located downstream of PKC in the regulation of early growth response factor 1 (Egr-1) (Fig. 3A and B)
Summary
Tissue factor (TF) is an important protein, as the key trigger of the coagulation cascade, and as a mediator in the pathogenesis of cardiovascular disorders. Hyperglycaemia is a major contributor to the cardiovascular diseases associated with diabetes. Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis, largely because of an increase in the levels of several pro-coagulation factors (e.g. fibrinogen, factor VII and von Willebrand factor) and a decrease in the levels of several anticoagulation factors (e.g. antithrombin III and protein C) [6]. Atherothrombosis accounts for the majority of deaths in patients with DM [7].
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