Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

Abstract

Oxidative stress is one of the characteristics of diabetes and is thought to be responsible for many of the pathophysiological changes caused by the disease. We previously identified an insulin response element in the promoter of plasminogen activator inhibitor 1 (PAI-1) that was activated by an unidentified member of the forkhead/winged helix (Fox) family of transcription factors. This element mediated a 5-7-fold increase in PAI-1 transcription because of insulin. Here we report that oxidative stress also caused a 3-fold increase in PAI-1 transcription and that the effect was additive with that of insulin. Antioxidants prevent this response. Mutational analysis of the PAI-1 promoter revealed that oxidative stress acted at an AP-1 site at ؊60/52 of the promoter. Gel mobility shift analysis demonstrated that binding to an AP-1 oligonucleotide was increased 4-fold by oxidative stress. Jun levels were increased by oxidants as assessed by reverse transcriptase-PCR. Western blotting demonstrated that a rapid and prolonged nuclear accumulation of phospho-c-Jun followed oxidant stimulation. The nuclear c-Jun phosphorylation was not observed in cells treated with reduced glutathione. Finally, JNK/SAPK activity was found to increase in response to oxidants, and inhibition of JNK/SAP blocked TBHQ-increased PAI-1-luciferase expression. Thus, oxidative stress stimulated AP-1 and activated the PAI-1 promoter.

Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARγ and c-Jun

“…It is likely that reduction of oxidative stress was also responsible for the protective effect of metallothionein on cardiac contractile dysfunction associated with insulin resistance, a notion supported by its antagonism against the sucrose-diet-induced reduction of GSH : GSSG ratio and against hyperphosphorylation of the transcription factor c-Jun, a key signalling molecule stimulated by enhanced oxidative stress [37]. C-Jun is a unique transcription factor controlling cell survival through regulation of cell cycle regulators such as p53, p21 and p16 [37].…”

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

“…Induction of PAI-1 expression by hypoxia involves the transcription factors, HIF-1␣, early growth response factor 1 (Egr-1), and CCAAT/enhancer-binding protein ␣ (C/EBP␣) (20). Oxidative stress regulates PAI-1 expression through activator protein (AP-1) (25). Little is known regarding plasma factors that lead to the elevated expression of PAI-1 in SCD.…”

Virgin olive oil in preventive medicine: From legend to epigenetics

“…The phenols, on the other hand, in addition to protecting both humans and experimental animal models from the harmful action of free radicals and reducing TXB2, also inhibit platelet aggregation and alteration of the platelet/vascular wall, reduce fibrinogen, factor VII and the principal suppressant of hemostasis (plasminogen activator inhibitor type 1, or PAI-1), thereby increasing fibrinolysis [44][45][46][47][48][49]. The anti-thrombotic role of EVOO phenols in addition to their antioxidant and anti-inflammatory properties are well characterized, was and they has been demonstrated to reduce TXB2 and LTB4 after a meal containing high quantities of EVOO [47].…”

“…Oleic acid [20] Inhibition of platelet aggregation and alteration of the platelet/vascular wall, reduction of fibrinogen, factor VII and the principal suppressant of hemostasis, thereby increasing fibrinolysis Phenolic compounds [44][45][46][47][48][49] Reduction of TXB2 and LTB4 in both hyperlipaemic subjects and patients with type 2 diabetes [44,50] Chemo-protective action and improvement of the endothelium function Phenolic compounds (hydroxytyrosol and tyrosol) [44,50] Preventive action against thrombotic and microthrombotic events in patients with type 2 diabetes and hyperlipaemic subjects Hydroxytyrosol [44,50] Reduction of risks for patients with cardiac pathologies [25] Oxidation and oxidative stress Maintenance of cellular integrity and reduction of ageing High level of oleic acid and lack of excess of linoleic acid [56] Anti-inflammatory and vasodilatative action a-linolenic acid (ALA) [60] Delay of atherosclerosis Phenolic compounds [16,44,59, 60] Prevention of oxidation of cells-membrane lipids and plasma lipoproteins, reducing the risk of atherosclerosis Tocopherols [43,60] Reduced production of free radicals and prevention of damages to the cellular membrane, mitochondria, and DNA, with beneficial effects on aging and cancer risk [66,67] Inflammation Anti-inflammatory action by non-selectively inhibition of the COX-1 and COX-2 enzymes Oleocanthal [38,69] Protection against various pathological conditions (10 types of tumors including colon, stomach, breast, prostate, lung, and Alzheimer's disease) Oleocanthal [72,73,78] Obesity and diabetes Reduction of risk by inhibition of the activation of NF-kB at the cellular level Phenols, carotenoids, and tocopherols [60,92] Protective action on mitochondria, reduced production of free radicals and protection against DNA oxidation [60,…”