In vivo thromboxane-dependent platelet activation is persistently enhanced in subjects with impaired glucose tolerance.

Background: Impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality. Enhanced thromboxane (TX)-dependent platelet activation plays a pivotal role in atherothrombosis and characterizes type 2 diabetes mellitus (DM). Whether this also pertains to IGT is currently unknown.

Aspirin and renal insufficiency progression in patients with atrial fibrillation and chronic kidney disease.

Background: In experimental models, thromboxane (Tx)A reduced renal perfusion and accelerated renal failure. The aim of the study was to investigate the association between the use of aspirin, which inhibits TxA production, and the incidence of an estimated Glomerular Filtration Rate (eGFR) <60 and <45ml/min/1.73m in patients with atrial fibrillation (AF) and chronic kidney disease (CKD).

Oxidative stress in chronic vascular disease: From prediction to prevention.

This review article is intended to describe the strong relationship between oxidative stress and vascular disease. Reactive oxygen species (ROS) play an important role in the pathogenesis of vascular disease: oxidative stress is intimately linked to atherosclerosis, through oxidation of LDL and endothelial dysfunction, to diabetes, mainly through advanced glycation end-products (AGEs)/receptor for AGE (RAGE) axis impairment, protein kinase C (PKC), aldose reductase (AR) and NADPH oxidase (NOX) dysfunction, and to hypertension, through renin–angiotensin system(RAS) dysfunction. Several oxidative stress biomarkers have been proposed to detect oxidative stress levels and to improve our current understanding of the mechanisms underlying vascular disease.

Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective.

Observational studies consistently reported an association between plasma total homocysteine concentrations and the risk of vascular events. In contrast, data from randomized trials largely support the hypothesis that mild elevations in homocysteine level have a modest effect on cardiovascular risk. A substantial body of evidence suggests that platelet activation is, at least in part, a transducer of the effects of high homocysteine in promoting atherothrombosis.

Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk.

Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment.

Background: Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events.

CD40/CD40L system and vascular disease.

Several distinct lines of investigation in the context of atherosclerosis dealing with low-grade inflammation, oxidative stress and platelet activation are now emerging, with CD40/CD40L system as the missing link. CD40 ligand is a transmembrane glycoprotein structurally related to tumour necrosis factor-alpha and more than 95% of the circulating CD40L derives from platelets. CD40L appears as a multiplayer of several cell types in the inflammatory network.

Relationship between reduced BCL-2 expression in circulating mononuclear cells and early nephropathy in type 1 diabetes.

Microalbuminuria is the earliest clinical evidence of diabetic nephropathy, but the mechanisms linking hyperglycemia and kidney complications are not clear. The aim of this study was to evaluate whether enhanced oxidative stress in patients with microalbuminuria can contribute to diabetic nephropathy development through downregulation of the antiapoptotic gene Bcl-2 that promotes in turn a pro-inflammatory status. We studied 30 patients with type 1 diabetes (15 with and 15 without microalbuminuria) compared to 15 matched healthy controls.

Identification and analysis of the promoter region of the human methionine sulphoxide reductase A gene.

MsrA (methionine sulphoxide reductase A) is an antioxidant repair enzyme that reduces oxidized methionine to methionine. Moreover, the oxidation of methionine residues in proteins is considered to be an important consequence of oxidative damage to cells. To understand mechanisms of human msrA gene expression and regulation, we cloned and characterized the 5' promoter region of the human msrA gene.

Lipid peroxidation in diabetes mellitus.

There is considerable evidence that hyperglycemia represents the main cause of complications of diabetes mellitus (DM), and oxidative stress resulting from increased generation of reactive oxygen species plays a crucial role in their pathogenesis. In fact, in the absence of an appropriate response from endogenous antioxidant mechanisms, the redox imbalance causes the activation of stress-sensitive intracellular signaling pathways. The latter play a key role in the development of late complications of DM, as well as in mediating insulin resistance (i.

Increased soluble CD40 ligand levels in cystic fibrosis.

Chronic inflammation represents a key pathogeneric event in the progression of lung disease in cystic fibrosis (CF). To identify novel mechanisms of the inflammatory reaction in CF and analyze its relation with coagulative activation, we carried-out a cross-sectional study to evaluate circulating levels of the inflammatory mediators soluble (s) CD40L, C-reactive protein (CRP), interleukin (IL)-1beta, the coagulation markers activated factor VII (FVIIa) and prothrombin fragment (F) 1+2, as well as urinary 11-dehydro-thromboxane (TX)B2, an index of in vivo platelet activation, in 34 CF patients and 34 matched healthy subjects. We observed that CF patients displayed significantly increased circulating levels of sCD40L compared to controls [2.

Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty.

Background: Inflammation plays a pathogenic role in the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). CD40-CD40L interaction is involved in the pathogenesis of atherosclerosis; however, its role in the pathophysiology of restenosis is still unclear. We tested the hypothesis that soluble CD40L (sCD40L) may be involved in the process of restenosis and that it exerts its effect by triggering a complex group of inflammatory reactions on endothelial and mononuclear cells.

The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control.

Background: RAGE (receptor for advanced glycation end products [AGEs]) plays a role in diabetic atherosclerosis. Recently, we have demonstrated enhanced expression of cyclooxygenase-2 and PGE synthase-1 (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. However, the specific transmembrane signaling pathway(s) influencing plaque COX-2/mPGES-1 expression is unknown.

High preprocedural non-HDL cholesterol is associated with enhanced oxidative stress and monocyte activation after coronary angioplasty: possible implications in restenosis.

Objective: To investigate whether enhanced oxidant stress in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) is associated with a higher concentration of non-high density lipoprotein (HDL) cholesterol at baseline, and whether this contributes to the inflammatory reaction and luminal renarrowing after PTCA.

Design: An ex vivo and in vitro study of 46 patients who underwent PTCA and who had repeat angiograms after six months. Blood samples were collected immediately before PTCA, and at 24 hours, 48 hours, and 15 days after.

Modulation of aspirin-insensitive eicosanoid biosynthesis by 6-methylprednisolone in unstable angina.

Background: The evidence that inflammation plays a pivotal role in the pathophysiology of acute coronary syndromes prompted us to investigate the effects of glucocorticoid treatment on leukotriene (LT) C4 and thromboxane (TX) A2 biosynthesis in unstable angina.

Methods And Results: Urinary LTE4 and 11-dehydro-TXB2 were significantly higher in 12 patients with unstable angina than in 12 patients with stable angina and 12 patients with nonischemic chest pain. Furthermore, we randomized the unstable angina patients to receive intravenous 6-methylprednisolone (6-MP; 1 mg/kg BID for 2 days) or matching placebo and collected 12 consecutive 6-hour urine samples before and during the infusions.

Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy.

Background: Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins.

Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty.

Inflammation plays a pathogenic role in the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant of monocytes; however, its role in the pathophysiology of restenosis is still unclear. We set out to investigate the role of MCP-1 in restenosis after PTCA.

Aspirin: new cardiovascular uses for an old drug.

Inhibition of TXA2-dependent platelet function by aspirin may lead to prevention of thrombosis as well as to excess bleeding. The balance between the two depends critically on the absolute thrombotic versus hemorrhagic risk of the patient. As the risk of experiencing a major vascular event increases, so does the absolute benefit of antiplatelet prophylaxis with aspirin [Figure-see text].

Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm.

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between hyperglycemia and the development of complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that oxidative stress may play a key role in the etiology of diabetic complications.

Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina.

Background: Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F(2)-isoprostane 8-iso-prostaglandin (PG)F(2alpha), a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis.

Effects of vitamin E supplementation on F(2)-isoprostane and thromboxane biosynthesis in healthy cigarette smokers.

Background: Increased formation of 8-iso-prostaglandin (PG) F(2alpha) and thromboxane (TX) A(2), potent agonists of platelet and vascular thromboxane (TH)/PGH(2) receptors, has been detected in cigarette smokers. We performed a randomized, double-blind, placebo-controlled study of the effects of vitamin E (300, 600, and 1200 mg/d, each dose for 3 consecutive weeks) on 8-iso-PGF(2alpha) and TXA(2) biosynthesis in 46 moderate cigarette smokers.

Methods And Results: Urinary immunoreactive 8-iso-PGF(2alpha) and 11-dehydro-TXB(2), plasma vitamin E, and serum TXB(2) were measured by previously validated techniques.

Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects.

We evaluated whether therapeutic blood levels of meloxicam are associated with selective inhibition of monocyte cyclooxygenase (COX)-2 in vitro and ex vivo. Concentration-response curves for the inhibition of monocyte COX-2 and platelet COX-1 were obtained in vitro after the incubation of meloxicam with whole blood samples. Moreover, 11 healthy volunteers received placebo or 7.