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

Title
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
Author(s)
강영진하유미[하유미]장기철[장기철]박은정[박은정]김혜정[김혜정]박상원[박상원]
Keywords
PROTEIN-KINASE; SKELETAL-MUSCLE; INSULIN-RESISTANCE; RISK-FACTORS; ANGIOTENSIN; INFLAMMATION; PATHWAY; MONOCYTES; DISEASE; ATHEROSCLEROSIS
Issue Date
201410
Publisher
WILEY-BLACKWELL
Citation
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, v.18, no.10, pp.2031 - 2043
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 (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, 15mM) 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-B and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-, IL-6 and IL-1) production and NF-B 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 (20mg/kg, i.p) for 8weeks 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.
URI
http://hdl.handle.net/YU.REPOSITORY/30604http://dx.doi.org/10.1111/jcmm.12354
ISSN
1582-4934
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의과대학 > 약리학교실 > Articles
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