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ABSTRACT: Atherothrombosis is the major determinant of acute ischaemic cardiovascular events, such as myocardial infarction and stroke. Inflammatory processes have been linked to all phases of atherogenesis In particular, the identification of autoimmunity mediators in the complex microenvironment of chronic inflammation has become the focus of attention in both early and advanced atherogenic processes. Auto-antibodies against self-molecules or new epitopes generated by oxidative processes infiltrate atherosclerotic plaques and were shown to modulate the activity of immune cells by binding various types of receptors. However, despite mounting evidence for a pathophysiological role of autoantibodies in atherothrombosis, the clinical relevance for circulating autoantibodies in cardiovascular outcomes is still debated. This review aims at illustrating the mechanisms by which different types of autoantibodies might either promote or repress atherothrombosis and to discuss the clinical studies assessing the role of auto-antibodies as prognostic biomarkers of plaque vulnerability.
Thrombosis and Haemostasis 02/2013; 109(5). · 5.04 Impact Factor
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N Vuilleumier, F Montecucco,
G Spinella,
S Pagano,
M Bertolotto,
B Pane,
A Pende,
K Galan,
P Roux-Lombard,
C Combescure,
F Dallegri,
F Mach,
D Palombo
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ABSTRACT: We aimed at challenging the prognostic accuracies of myeloperoxidase (MPO) and antibodies anti-apolipoprotein A-1 (anti-apoA-1 IgG), alone or in combination, for major adverse cardiovascular events (MACE) prediction, one year after carotid endarterectomy (CEA). In this prospective single centre study, 178 patients undergoing elective CEA were included. Serum anti-apoA-1 IgG and MPO were assessed by enzyme-linked immunosorbent assay prior to the surgery. Post-hoc determination of the MPO cut-off was performed by receiver operating characteristics (ROC) analyses. MACE was defined by the occurrence of fatal or non-fatal acute coronary syndromes or stroke during one year follow-up. Prognostic accuracy of anti-apoA-1 IgG was assessed by ROC curve analyses, survival analyses and reclassification statistics. During follow-up, 5% (9/178) of patients presented a MACE, and 29% (52/178) were positive for anti-apoA-1 IgG. Patients with MACE had higher median MPO and anti-apoA-1 IgG levels at admission (p=0.01), but no difference for the 10-year global Framingham risk score (FRS) was observed (p=0.22). ROC analyses indicated that both MPO and anti-apoA-1 IgG were significant predictors of subsequent MACE (area under the curve [AUC]: 0.75, 95% confidence interval [95%CI]: 0.61-0.89, p=0.01; and 0.74, 95%CI: 0.59-90; p=0.01), but combining anti-apoA-1 IgG positivity and MPO>857 ng/ml displayed the best predictive accuracy (AUC: 0.78, 95%CI: 0.65-0.91; p=0.007). It was associated with a poorer MACE-free survival (98.2% vs. 57.1%; p<0.001, LogRank), with a positive likelihood ratio of 13.67, and provided incremental predictive ability over FRS. In conclusion, combining the assessment of anti-apoA-1 IgG and MPO appears as a promising risk stratification tool in patients with severe carotid stenosis.
Thrombosis and Haemostasis 01/2013; 109(4). · 5.04 Impact Factor
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ABSTRACT: Thrombosis is a rare but serious complication of stent implantation in atherosclerotic arteries, affecting both bare-metal and drug-eluting stents. Diagnostic criteria for stent thrombosis have recently been updated with the time and probability of the event being considered as crucial parameters. To be considered as "definite", the diagnosis of stent thrombosis has to be confirmed by angiography or histology. This statement position has clearly rendered more difficult the clinical assessment of stent thrombosis in randomised clinical trials. Considering these limitations, stent thrombosis represents a dramatic complication for both patients and cardiologists. In coronary plaques, thrombosis is often associated with death, acute coronary syndromes and arrhythmias. For these reasons, the pharmacological improvement of this outcome represents a "hot-topic" field for research. Among several medications, statins have been shown to potentially reduce the incidence of coronary stent thrombosis in humans. However, randomised clinical trials focussing on "definite" diagnosis are still needed to confirm these promising results. In addition, the use of statins in patients implanted with stents in other arteries is largely unexplored. Finally, statin-eluting stents (only tested in pigs) have to be evaluated in other animal models and human beings. Therefore, a clear recommendation on the use of statins to prevent stent thrombosis is not available and caution should be used. The "pleiotropic" anti-atherosclerotic properties of statins might represent a crucial investigation field to pathophysiologically clarify the role of statins in stent complications.
Schweizerische medizinische Wochenschrift 01/2012; 142:w13525. · 1.68 Impact Factor
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Alessandra Quercioli,
François Mach,
Maria Bertolotto,
Sébastien Lenglet,
Nicolas Vuilleumier,
Katia Galan,
Sabrina Pagano,
Vincent Braunersreuther,
Graziano Pelli,
Vito Pistoia, [......],
Giuseppe Cittadini,
Giorgio Luciano Viviani,
Aldo Pende,
Pascale Roux-Lombard,
Aurélien Thomas,
Christian Staub,
Osman Ratib,
Franco Dallegri,
Thomas Helmut Schindler, Fabrizio Montecucco
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ABSTRACT: The "blood vulnerability", resulting from the complex balance between serum molecules and inflammatory cell atherosclerotic activities, is a major determinant in the evaluation of the "global patient cardiovascular vulnerability". In the present study, we focused on the role of the soluble receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL, a potential marker of coronary calcification and vulnerability) in the release of neutrophilic proteases. Then, the association between these mediators and the degree of coronary calcification (assessed by coronary calcium score [CCS]) was investigated in 20 subjects (aged ≥65 years) asymptomatic for cardiovascular disease. Results showed that RANKL dose-dependently induced matrix metalloprotease (MMP)-8 and MMP-9 release from human primary neutrophils cultured in Teflon dishes (suspension condition, mimicking cells circulating in the blood stream). Conversely, when adherent to polystyrene, neutrophils became unresponsive to RANKL. RANKL did not influence the release of other neutrophilic products in suspension and adherence cultures as well as neutrophil migration. RANKL-induced release of MMPs was dependent on the activation of defined intracellular signalling pathways (PI3K/Akt and ERK1/2). In asymptomatic subjects, serum levels of RANKL, MMP-8 and MMP-9 positively correlated with CCS, reflecting a potential relationship between circulating RANKL and coronary calcification. In conclusion, RANKL increased the release of neutrophilic products potentially related to the "blood" vulnerability via defined intracellular pathways. Serum levels of RANKL might represent a potential biomarker of coronary calcification and related cardiovascular risk.
Thrombosis and Haemostasis 11/2011; 107(1):124-39. · 5.04 Impact Factor
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ABSTRACT: The definition of ischaemic stroke has been recently updated as an acute episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia in the presence of a cerebral infarction. This "tissular" definition has highlighted the importance of pathophysiological processes underlying cerebral damage. In particular, post- ischaemic inflammation in the brain and in the blood stream could influence crucial steps of the tissue injury/repair cascade. CC and CXC chemokines orchestrate the inflammatory response in atherosclerotic plaque vulnerability and cerebral infarction. These molecules exert their activities through the binding to selective transmembrane receptors. CC and CXC chemokines modulate crucial processes (such as inflammatory cell recruitment and activation, neuronal survival, neoangiogenesis). On the other hand, CXC chemokines could also modulate stem cell homing, thus favouring tissue repair. Given this evidence, both CC and CXC chemokines could represent promising therapeutic targets in primary and secondary prevention of ischaemic stroke. Only preliminary studies have been performed investigating treatments with selective chemokine agonists/antagonists. In this review, we will update evidence on the role and the potential therapeutic strategies targeting CC and CXC chemokines in the pathophysiology of ischaemic stroke.
Thrombosis and Haemostasis 12/2010; 105(3):409-20. · 5.04 Impact Factor
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ABSTRACT: During the last 15 years, a growing body of evidence supported the fact that auto-antibodies represent not only emergent markers but also active mediators of cardiovascular disease (CVD), clinically represented mostly by acute coronary syndrome (ACS) and stroke. There is a contrasted relationship between auto-antibodies and CVD, some being protective, while others acting as potential risk factors. Therefore, we performed a review of the literature on the respective cardiovascular prognostic value of the most relevant auto-antibodies in ACS and stroke, and their putative pathophysiological properties in atherogenesis. This review highlights auto-antibodies as active modulators of the innate immune system in atherogenesis (either toward a pro- or anti-inflammatory response), or by affecting basal heart rate regulation (anti-apoA-1 IgG). Given their apparent prognostic independency towards traditional cardiovascular risk factors, the data available in the literature indicates that some of those auto-antibodies could be of valuable help for cardiovascular risk stratification in the future, especially because their deleterious effects have been shown to be potentially abrogated in vivo and in vitro by existing therapeutic modalities. Although evidence in humans is currently lacking, these studies may open innovative therapeutic perspectives for CVD in the future.
Clinical Reviews in Allergy & Immunology 12/2010; · 3.68 Impact Factor
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ABSTRACT: Non-uniformity exists on heart failure definitions. Heart failure includes typical signs and symptoms deriving from alterations in left ventricular systolic or diastolic function. Systolic heart failure results from the acute or chronic reduction of the left ventricular ejection fraction. Conversely, heart failure with preserved ejection fraction is characterized by excessive myocardial fibrosis and cardiomyocyte hypertrophy that cause reduced left ventricular relaxation. Both heart failure subtypes cause identical symptoms and signs. Clinical and laboratory tests assist in the diagnosis of systolic heart failure or heart failure with preserved ejection fraction (diastolic heart failure) and can help in the identification of different causes of the disease and comorbidities. In the last two decades, the renin-angiotensin system (RAS) has been identified as a crucial regulator in all phases of systolic and diastolic heart failure. Although several studies are needed to further clarify this issue, three different levels (systemic, intracardiac and intracellular) for renin pathophysiological activity have been identified. In particular, the direct role of intracellular renin on subcellular cardiomyocyte remodeling could be considered as a very fruitful investigation field. Several ongoing clinical studies will probably clarify the role of renin inhibitors in heart failure. The ancient theory of Skeggs and coworkers on direct renin inhibition to block the RAS cascade effects could be confirmed in future studies.
Panminerva medica 03/2010; 52(1):41-51. · 1.11 Impact Factor
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ABSTRACT: 1. Chlorhexidine digluconate has been used as a topical antiseptic in the treatment of acne vulgaris and periodontitis. The acute phase of these diseases involves neutrophilic infiltration. Neutrophil activation and recruitment to inflammatory sites are crucial in both protection against bacterial infection and the induction of hystotoxic damage. Activated neutrophils release several enzymes, including elastase and myeloperoxidase (MPO), which contribute to tissue injury via direct toxic actions, the generation of oxidants and inactivation of protective factors, such as alpha1-antitrypsin (alpha1-AT). In the present study, we investigated whether chlorhexidine can modulate neutrophil-mediated histotoxicity. 2. Human primary neutrophils were isolated from healthy donors. Inactivation of alpha1-AT by neutrophils or hypochlorous acid (HOCl) was evaluated by spectrophotometry and sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis of its capacity to complex with porcine pancreatic elastase (PPE). Neutrophil generation of HOCl, superoxide anion and MPO release were assessed spectrophometrically. 3. Chlorhexidine (0, 0.5, 1, 5 and 10 micromol/L) dose-dependently prevented HOCl-induced inactivation of alpha1-AT and reduced HOCl recovery from phorbol myristate acetate (PMA)-treated human neutrophils, but did not inhibit superoxide anion and MPO release. Chlorhexidine directly inhibited HOCl recovery from neutrophils and HOCl-induced inactivation of alpha1-AT in a cell-free assay. Accordingly, chlorhexidine reversed HOCl-mediated inhibition of alpha1-AT capacity to complex with PPE. 4. These data suggest that chlorhexidine prevents neutrophil-induced alpha1-AT inactivation via a direct inhibitory action on HOCl. Although highly speculative, the present study indicates that chlorhexidine may protect inflamed tissues not only through its antimicrobial properties, but also via a direct anti-inflammatory effect on neutrophil toxic products.
Clinical and Experimental Pharmacology and Physiology 09/2009; 36(11):e72-7. · 1.85 Impact Factor
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ABSTRACT: 1. Neutrophils release several histotoxic molecules that cause tissue injury. Neutrophil apoptosis is a crucial process that governs the persistence of inflammatory disorders and tissue damage. Thus, in the present study, we investigated whether the anti-inflammatory drug sulphasalazine (SSZ) affects neutrophil apoptosis in the presence of insoluble immune complex (IC). 2. Neutrophils were obtained from healthy donors. Neutrophils were resuspended in incubation medium and incubated for 2-12 h with or without 10, 30 or 100 micromol/L SSZ and 25 microg/mL IC. In some experiments, cells were co-incubated with 20 micromol/L Z-IETD-fmk (a caspase 8 inhibitor) or 20 micromol/L Z-LEHD-fmk (a caspase 9 inhibitor). Apoptosis was evaluated morphologically on cytological preparations stained with May-Grünwald-Giemsa as well as by flow cytometry analysis of annexin V and propidium iodide staining. Caspase 3 activity was determined spectrophotometrically. 3. At 100 micromol/L, SSZ significantly accelerated IC-induced neutrophil apoptosis. Treatment of neutrophils with 20 micromol/L of the caspase 8 or 9 inhibitors Z-IETD-fmk or Z-LEHD-fmk, respectively, demonstrated that the SSZ-induced pro-apoptotic effect was mediated by a caspase 8- but not caspase 9-dependent pathway. The caspase 3 activity assay showed that treatment with 100 micromol/L SSZ increased caspase 3 activation. 4. In conclusion, the results of the present study indicate that it is possible that the molecular mechanism underlying SSZ protection against neutrophil-mediated tissue injury inflammatory disorders, such as rheumatoid arthritis and inflammatory bowel diseases, involves a caspase 8-dependent pathway.
Clinical and Experimental Pharmacology and Physiology 06/2009; 36(11):1132-5. · 1.85 Impact Factor
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ABSTRACT: We have recently shown that CRP induces chemokine secretion and adhesion molecule up-regulation in human primary monocytes cultured in adherence. Given the increasing evidence on direct immunomodulatory properties of statins, we investigated their possible anti-inflammatory role on CRP-treated human monocytes.
Monocytes were isolated by Ficoll-Percoll gradients and cultured in adherence to polystyrene. Chemokine secretion and adhesion molecule expression were detected by ELISA and flow cytometry. Migration assays were performed in modified Boyden chambers. Intracellular kinase activation was assessed by western blot.
Treatment with simvastatin or atorvastatin decreased CRP-induced release of CCL2, CCL3 and CCL4. In addition, both statins reduced CRP-induced intercellular adhesion molecule (ICAM-1) up-regulation, but had no effects on CD11b and CD18. Treatments with 1 microM simvastatin or atorvastatin significantly inhibited monocyte migration in response to CRP. CD32 and CD64 (CRP receptors) expression on monocytes was not affected by statins. Statin-induced inhibition of CRP-mediated chemokine secretion, ICAM-1 up-regulation and migration occurred through the inhibition of extracellular signal-regulated kinase (ERK) 1/2. Treatment with L-mevalonate or farnesylpyrophosphate, but not geranylgeranyl-pyrophosphate reversed the statin-induced effect on CRP-mediated functions and ERK 1/2 phosphorylation, confirming that statins blocked CRP-induced ERK 1/2 phosphorylation through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.
Statins inhibited CRP-induced chemokine secretion, ICAM-1 up-regulation and migration in human adherent monocytes, through the inhibition of HMG-CoA reductase-ERK 1/2 pathway. This pathway could represent a very promising target to reduce CRP-induced activities in monocyte-mediated diseases, such as atherosclerosis or RA.
Rheumatology (Oxford, England) 02/2009; 48(3):233-42. · 4.24 Impact Factor
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ABSTRACT: Changes in diagnostic criteria have impacted on the definition of the metabolic syndrome. The central aetiological importance of insulin resistance has lessened, while the role of other cardiovascular risk factors has progressively increased. Inflammatory mediators have also been identified as crucial targets for more selective therapies in metabolic syndrome. Among several pro-inflammatory factors, adiponectin has been shown to be associated with reduced cardiovascular risk in metabolic syndrome patients. Here, we review new therapeutic approaches, which could potentially increase adiponectin levels in metabolic syndrome.
Diabetes Obesity and Metabolism 11/2008; 11(5):445-54. · 3.38 Impact Factor
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ABSTRACT: RA is characterized by a systemic inflammatory state, in which immune cells and soluble mediators play a crucial role. These inflammatory processes resemble those in other chronic inflammatory diseases, such as atherosclerosis. The chronic systemic inflammation in RA can be considered as an independent risk factor for the development of atherosclerosis, and represents an important field to investigate the reasons of the increase of acute cardiovascular events in RA. In the present review, we focused on several mediators of autoimmunity, inflammation and endothelial dysfunction, which can be considered the most promising targets to prevent atherogenesis in RA. Among several mediators, the pro-inflammatory cytokine TNF-alpha has been shown as a crucial factor to induce atherosclerosis in RA patients.
Rheumatology (Oxford, England) 11/2008; 48(1):11-22. · 4.24 Impact Factor
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ABSTRACT: Atherosclerosis is a chronic inflammatory disease that is the primary cause of myocardial infarction and stroke, which occur after sudden thrombotic occlusion of an artery. A growing body of evidence suggests that cannabinoid signalling plays a fundamental role in atherosclerosis development and its clinical manifestations. Thus, CB2 receptors are protective in myocardial ischaemia/reperfusion and implicated in the modulation of chemotaxis, which is crucial for the recruitment of leukocytes during inflammation. Delta-9-Tetrahydrocannabinol (THC)-mediated activation has been shown to inhibit atherosclerotic plaque progression in a CB2 dependent manner. Although CB1 and CB2 expression has been reported on platelets, their involvement in thrombus formation is still controversial. While several reports suggest that CB1 receptors may have a relevant role in neuroprotection after ischaemic stroke, recent studies show the protective effects in various forms of neuroprotection are not related to CB1 stimulation, and a protective role of CB1 blockade has also been reported. In addition, vascular and myocardial CB1 receptors contribute to the modulation of blood pressure and heart rate. It is tempting to suggest that pharmacological modulation of the endocannabinoid system is a potential novel therapeutic strategy in the treatment of atherosclerosis. For these purposes, it is important to better understand the complex mechanisms of endocannabinoid signalling and potential consequences of its pharmacological modulation, as it may have both pro- and anti-atherosclerotic effects.
British Journal of Pharmacology 02/2008; 153(2):290-8. · 4.41 Impact Factor
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ABSTRACT: Monocytes and macrophages play a key role in the initiation and persistence of inflammatory reactions. The possibility to interfere with the survival of these cells, once recruited and activated at sites of inflammation, is an attractive therapeutic option. Although resting monocytes are susceptible to pharmacologically induced apoptosis, no data are available about the possibility to modulate the survival of activated monocytes. The present work was planned to investigate if dexamethasone is able to promote apoptosis of human monocytes activated by immune complexes. When monocytes were cultured with immune complexes, a dose-dependent inhibition of apoptosis was observed. Dexamethasone stimulated apoptosis of resting and activated monocytes in a dose-dependent manner. Both the immune complex inhibitory activity and dexamethasone stimulatory properties depend on NF-kappaB/XIAP and Ras/MEK/ERK/CD95 pathways. In fact, the exposure of monocytes to immune complexes increased NF-kB activation and XIAP expression, which in turn were inhibited by dexamethasone. On the other hand, immune complex-stimulated monocytes displayed a reduced expression of CD95, which is prevented by dexamethasone, as well as by MEK inhibitor U0126. Furthermore, anti-CD95 ZB4 mAb prevented dexamethasone-induced apoptosis in immune complex stimulated monocytes. Similarly, ZB4 inhibited dexamethasone-mediated augmentation of caspase 3 activity. The present findings suggest that Fc triggering by insoluble immune complexes result in the activation of two intracellular pathways crucial for the survival of monocytes: 1. Ras/MEK/ERK pathway responsible for the down-regulation of CD95 expression; 2. NF-kappaB pathway governing the expression of XIAP. Both the pathways are susceptible to inhibition by monocyte treatment with pharmacologic concentrations of dexamethasone.
International journal of immunopathology and pharmacology 18(3):403-15. · 2.99 Impact Factor
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A. Quercioli,
F. Mach,
M. Bertolotto,
S. Lenglet,
N. Vuilleumier,
K. Galan,
S. Pagano,
V. Braunersreuther,
G. Pelli,
V. Pistoia, [......],
G. Cittadini,
G. L. Viviani,
A. Pende,
P. Roux-Lombard,
A. Thomas,
C. Staub,
O. Ratib,
F. Dallegri,
T. H. Schindler, F. Montecucco
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[hide abstract]
ABSTRACT: The "blood vulnerability", resulting from the complex balance between serum molecules and inflammatory cell atherosclerotic activities, is a major determinant in the evaluation of the "global patient cardiovascular vulnerability". In the present study, we focused on the role of the soluble receptor activator of nuclear factor kappa-B (NF-kappaB) ligand (RANKL, a potential marker of coronary calcification and vulnerability) in the release of neutrophilic proteases. Then, the association between these mediators and the degree of coronary calcification (assessed by coronary calcium score [CCS]) was investigated in 20 subjects (aged >/=65 years) asymptomatic for cardiovascular disease. Results showed that RANKL dose-dependently induced matrix metalloprotease (MMP)-8 and MMP-9 release from human primary neutrophils cultured in Teflon dishes (suspension condition, mimicking cells circulating in the blood stream). Conversely, when adherent to polystyrene, neutrophils became unresponsive to RANKL. RANKL did not influence the release of other neutrophilic products in suspension and adherence cultures as well as neutrophil migration. RANKL-induced release of MMPs was dependent on the activation of defined intracellular signalling pathways (PI3K/Akt and ERK1/2). In asymptomatic subjects, serum levels of RANKL, MMP-8 and MMP-9 positively correlated with CCS, reflecting a potential relationship between circulating RANKL and coronary calcification. In conclusion, RANKL increased the release of neutrophilic products potentially related to the "blood" vulnerability via defined intracellular pathways. Serum levels of RANKL might represent a potential biomarker of coronary calcification and related cardiovascular risk.
Thrombosis and haemostasis. 107(1):124-39.
