Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

Abstract

Introduction-Thrombomodulin (TM) is an important anti-coagulant protein that is downregulated on endothelial cells overlying atherosclerotic plaques. We investigated the effects of the peroxisome proliferator-activated receptor (PPAR) ligands, fenofibrate and rosiglitazone, on the expression of TM ex vivo by advanced carotid atheromas, and in vitro by endothelial cells.

Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma <i>in vitro </i>

“…MMP-2, -3, -9, TIMP-1, -2, -4, ATR1, ATR2, ERK1-P, ERK2-P and ERK1/2 expression and MMP-2 and -9 relative activation and overall catalytic capacity in the paired explant samples are presented as mean SEM for the relative ratios of paired experimental and control samples (n 14 or 12 pairs) 28,[32][33][34][35] . Differences between experimental and control samples were assessed using Wilcoxon's paired test in SPSS v21 software.…”

“…To minimise the impact of any medications the patient may have been receiving, a 24h preincubation step is included before the intervention study itself. We have previously shown the combination of these techniques minimises the heterogeneity between paired blockade and control samples 28,[32][33][34][35] . We also accept the potential for false discovery when many different outcomes are examined in the same samples.…”

“…The underlying regulatory mechanisms behind the pleomorphic beneficial outcomes of ATR1 blockade in atherosclerosis patients are also yet to be elucidated. In this study we aimed to clarify the roles of ATR1 and ATR2 in gelatinase regulation in carotid atheroma using paired human carotid atheroma explant culture 28,[32][33][34][35] and ATR blockers specific to type 1 or type 2.…”

A Nuclear Attack on Thrombosis and Inflammation

“…6 Cytokine-mediated suppression of thrombomodulin is achieved by activating nuclear factor-κB (NF-κB), which in turn sequesters p300/cAMP response element-binding protein, preventing it from binding to the thrombomodulin promoter. Like Nur77 and Nor1, tumor necrosis factor α-induced suppression of thrombomodulin can be offset by activation of several nuclear receptors, including the retinoic acid receptor-α, 7 the vitamin D receptor, 8 the peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ, 9,10 and the farnesoid X receptor, 11 as well as by the histone deacetylase, Sirt1 (Figure). 12 These can all induce expression of KLF-2 or KLF-4 and repress NF-κB pathway activity, and in turn enhance thrombomodulin gene transcription.…”

LXR agonist T0901317 upregulates thrombomodulin expression in glomerular endothelial cells by inhibition of nuclear factor-κB

“…The potential therapeutic value of TM modulation motivated the search for naturally abundant compounds that may regulate this vasoprotective molecule. Notably, previous studies determined that various nuclear receptors (NRs) were involved in the regulation of TM expression (3)(4)(5). However, the regulatory mechanism underpinning TM expression has yet to be fully elucidated.…”