Luciano Cominacini

University of Verona, Verona, Veneto, Italy

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Publications (130)607.62 Total impact

  • Chiara Mozzini · Giuseppe Roscia · Alder Casadei · Luciano Cominacini
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    ABSTRACT: Doppler ultrasound scanning is the first line investigation for quantifying the internal carotid artery stenosis. Nevertheless, the lack of internationally accepted ultrasound criteria for describing the degree of stenosis has contributed to the different and confusing measurements ranges. The use of two different angiographic methods, the North American Symptomatic Carotid Endoarterectomy Study and the European Carotid Surgery Trial was probably the major initial source of confusion in deriving valid and reliable duplex ultrasound criteria worldwide. The consensus proposed in 2003 by the Society of Radiologists in Ultrasound has been a great attempt to create a conformity document, establishing grey scale and Doppler criteria in considering the different degrees of stenosis. According to this attempt, in 2010, the multi-parametric Deutsche Gesellschaft für Ultraschall in der Medizin ultrasound criteria have been proposed with a precise differentiation between main and additional criteria and depicted a different peak systolic velocity (PSV) threshold. In 2012, these criteria have been implemented, focusing on the multi-parametric approach, re-defining the PSV values and clearly introducing the concept of PSV average. Despite these attempts, a wide range of practice patterns still exists, with consistent disparities in patients’ care. This paper collects these previous experiences and summarizes their strengths and weaknesses, to give a contribution in the carotid artery stenosis grading standardization using ultrasonic methods. Carotid ultrasound as the only diagnostic tool for the selection of patients for carotid surgery or stenting will be possible only with internationally accepted criteria.
    No preview · Article · Feb 2016
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: Qtracker(®)800 Vascular labels (Qtracker(®)800) are promising biomedical tools for high-resolution vasculature imaging; their effects on mouse and human endothelia, however, are still unknown. Qtracker(®)800 were injected in Balb/c mice, and brain endothelium uptake was investigated by transmission electron microscopy 3-h post injection. We then investigated, in vitro, the effects of Qtracker(®)800 exposure on mouse and human endothelial cells by calcium imaging. Transmission electron microscopy images showed nanoparticle accumulation in mouse brain endothelia. A subset of mouse and human endothelial cells generated intracellular calcium transients in response to Qtracker(®)800. Qtracker(®)800 nanoparticles elicit endothelial functional responses, which prompts biomedical safety evaluations and may bias the interpretation of experimental studies involving vascular imaging.
    Full-text · Article · Jul 2015 · Nanomedicine
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    ABSTRACT: Different cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein-folding capacity of the ER is overwhelmed. Reduction in blood flow as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the UPR fails to control the level of unfolded and misfolded proteins in the ER, ER-initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium following ischemia/reperfusion (I/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defence systems regulated by a series of multiple pathways, including UPR, to ensure that the response to oxidants is adequate. Nuclear factor-E2-related factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the UPR sensor called pancreatic endoplasmic reticulum kinase. A series of studies with interventions on ER stress and Nrf2 activation have been shown to reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload respectively. Finally, recent data reported that Nrf2/antioxidant response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon where the heart is subjected to one or more episodes of non-lethal myocardial I/R prior to the sustained coronary artery occlusion. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Free Radical Biology and Medicine
  • Francesco Spelta · Beatrice Bertozzi · Luciano Cominacini · Luigi Fontana

    No preview · Article · Mar 2015 · Vascular Pharmacology
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    Full-text · Dataset · Mar 2015
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    ABSTRACT: To evaluate the effects of supervised exercise training (SET) on cardiometabolic risk, cardiorespiratory fitness and oxidative stress status in 2 diabetes mellitus (T2DM), twenty male subjects with T2DM were randomly assigned to an intervention group, which performed SET in a hospital-based setting, and to a control group. SET consisted of a 12-month supervised aerobic, resistance and flexibility training. A reference group of ten healthy male subjects was also recruited for baseline evaluation only. Participants underwent medical examination, biochemical analyses and cardiopulmonary exercise testing. Oxidative stress markers (1-palmitoyl-2-[5-oxovaleroyl]-sn-glycero-3-phosphorylcholine [POVPC]; 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine [PGPC]) were measured in plasma and in peripheral blood mononuclear cells. All investigations were carried out at baseline and after 12 months. SET yielded a significant modification (p < 0.05) in the following parameters: V'O2max (+14.4%), gas exchange threshold (+23.4%), waist circumference (-1.4%), total cholesterol (-14.6%), LDL cholesterol (-20.2%), fasting insulinemia (-48.5%), HOMA-IR (-52.5%), plasma POVPC (-27.9%) and PGPC (-31.6%). After 12 months, the control group presented a V'O2max and a gas exchange threshold significantly lower than the intervention group. Plasma POVC and PGPC were significantly different from healthy subjects before the intervention, but not after. In conclusion, SET was effective in improving cardiorespiratory fitness, cardiometabolic risk and oxidative stress status in T2DM.
    Full-text · Article · Mar 2015 · Scientific Reports
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    ABSTRACT: Although the understanding the pathophysiology of atherogenesis and atherosclerosis progression has been one of the major goals of cardiovascular research during the last decades, the precise mechanisms underlying plaque destabilization are still unknown. The disruption of the plaque and the thrombosis in the lumen that are mostly determined by the expansion of the necrotic core (NC) are driven by various mechanisms, including accelerated macrophage apoptosis and defective phagocytic clearance (defective efferocytosis). Oxidative stress is implicated in the expansion of the NC: in fact, many oxidized compounds and processes contribute to the macrophage apoptosis; in addition, the oxidized derivatives of polyunsatured fatty acids promote defective efferocytosis, with the final result of NC expansion. In the last years the role of the endoplasmic reticulum (ER) stress is under investigation to better define its possible contribution in affecting the NC expansion. The abnormal amount of apoptotic cells in the vulnerable plaque has been demonstrated to be related both to the sustained ER stress and to the expression of survival and protective genes, such as the unfolded protein response or/and the nuclear erythroid- related factor 2. In this review the authors focus on the promising results of the oxidative and ER stress in contributing to the triggering and orchestrating the atherosclerotic plaque vulnerability.
    Full-text · Article · Mar 2015 · Current Medicinal Chemistry
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    ABSTRACT: ABSTRACT Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of type 2 diabetes mellitus (T2DM), with activation of the unfolded protein response (UPR) and ER- apoptosis in β cells. The study aim is investigating the role of the prolonged glycaemic, inflammatory and oxidative impairment as possible UPR and ER-apoptosis inductors in triggering the ER stress response and the protective Nrf2/ARE activation in peripheral blood mononuclear cells (PBMC) of T2DM patients without glycaemic target. Oxidative stress markers (oxidation product of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine, oxPAPC, and malondialdehyde, MDA), the UPR and ER apoptosis, the activation of the pro-inflammatory nuclear factor (NF)-kB with its inhibitory protein IkBα and the expression of the protective Nrf2 and heme -oxygenase-1 (HO-1) were evaluated in PBMC of 15 T2DM patients and 15 healthy controls (C). OxPAPC concentrations (in PBMC and plasma), MDA levels (in plasma), the expressions of the glucose-regulated protein 78 kDa (GRP78/BiP) as representative of UPR, and of the C/EBP homologous protein (CHOP) as representative of ER-apoptosis, were significantly higher (p<0.01) in T2DM respect to C. IkBα expression was significantly lower (p<0.01) in T2DM as well as Nrf2 and HO-1. In vitro experiments demonstrated that hyperglycaemic conditions, if prolonged, were NF-kB inductors, without a corresponding Nrf2/ARE response. In PBMC of T2DM without glycaemic target achievement there is activation of the UPR and of the ER apoptosis, that may be related to the chronic exposure to hyperglycaemia, to the augmented inflammation and to the augmented oxidative stress, without a corresponding Nrf2/ARE defence activation.
    No preview · Article · Dec 2014 · Free Radical Research
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    ABSTRACT: The importance of focused cardiac ultrasound (FCU) in Internal Medicine care has been recognized by the American Society of Echocardiography. The aim of this study was to test what realistic skill targets could be achieved in FCU, with a relatively short training (theoretical and practical) of 9 h offered to Internal Medicine certification board attending students, and if the addition of further 9 h of training could significantly improve the level of competence. Kappa statistic was used to calculate the inter-observer agreement (trainees/tutor). The agreement between the trainees (who completed the entire training) and the tutor was, respectively, “substantial” (k = 0.71) for the identification of pericardial effusion, “moderate” (k = 0.56–0.54) for the identification of marked right ventricular and left ventricular enlargement, “substantial” (k = 0.77) for the assessment of global cardiac systolic function by visual inspection and “fair” (k = 0.35) for the assessment of size and respiratory change in the diameter of the inferior cave vein (IVC). 18 h training in FCU provided proficiency in obtaining adequate images from the parasternal window without providing the ability to correctly master the apical and subcostal windows. As concerns the interpretative skills, only pericardial effusion and visual estimation of global systolic function could be correctly identified, while ventricular enlargement and IVC prove to be more difficult to evaluate. This study supports incorporating FCU into Internal Medicine fellowship training programs, and should facilitate the design of other similar training courses.
    No preview · Article · Dec 2014 · Internal and Emergency Medicine
  • S Adami · M Ferrari · G Galvanini · L Cominacini · F Bruni · M Pelloso · V Lo Cascio
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    ABSTRACT: Eight obese female patients were studied over a period of 15 days whilst on 300 kcal diet. Serum levels of thyroxine and free throxine index were not altered significantly by semistarvation. A TRH test performed before and after the diet showed no appreciable change. Weight loss was intially rapid but later slowed despite good patients compliance. Serum concentrations of T 3 and reverse T 3 (rT3) early decreased (p less than 0.01) and increased (p less than 0.05) respectively, but returned towards control levels even before discontinuation of semistarvation. There was a positive correlation between the percentage decrease in body weight and the percentage increase in serum rT 3 (p less than 0.001), and a negative correlation between decrease in body weight and decrease in serum T 3 (p less than 0.001). Our results do not suggest that the variations in serum triiodothyronines limit the weight loss; it is probable, on the contrary, that the weight loss promotes the observed variations in thyroid hormones by as yet unknown adaptive metabolic forces.
    No preview · Article · Jul 2014 · Journal of endocrinological investigation
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    ABSTRACT: Macrophage apoptosis is involved in atherosclerotic plaque development. The aim of this study was to evaluate the interrelationship between macrophage apoptosis and the endoplasmic reticulum (ER)-stress in the tissue around the necrotic core (TANC) and in the periphery (P) of the same carotid plaques derived from patients undergoing carotid endarterectomy. Apoptosis was significantly higher in TANC than in P (p<0.001). mRNA and protein expression of protein kinase-like ER kinase (Perk), and of the nuclear erythroid related factor 2 (Nrf2)-related survival genes were significantly higher in P than in TANC (p<0.01), while CCAAT/-enhancer binding protein homologous protein (Chop) and the apoptosis-related genes were higher in TANC than in P (p<0.01). TANC extract was characterized by significantly higher concentrations of oxidized derivatives of polyunsaturated fatty acids (PUFAs) than P extract (p<0.01). When THP-1 cells were incubated with P or TANC extracts there was a dose-dependent increase of Perk and Nrf2 or of Chop and of the apoptosis-related genes respectively (p<0.01). Our observations lead to the hypothesis that ER-stress induced by oxidized derivatives of PUFAs may promote macrophage apoptosis in TANC and favour the expansion of the necrotic core of the plaques, a major feature responsible for its disruption and acute luminal thrombosis.
    Full-text · Article · Mar 2014 · Antioxidants & Redox Signaling
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    ABSTRACT: In vitro 3T3-L1 mouse cells represent a reliable model to investigate the inflammatory phenotype of adipocytes activated by bacteria-derived lipopolysaccharide (LPS). In this study we have evaluated the differential expression of adipokines in response to increasing doses of LPS and various incubation times. 3T3-L1 mouse adipocytes were treated with E. coli LPS (from 0 to 10 μg/ml) for a time course ranging from 4 to 24 h, 4 h each. A time point at 2 h was also included to highlight early activation by LPS. mRNA expression by RT-PCR on cell lysates and ELISA assays on cell culture supernatants were performed. Cells activated by increasing doses of LPS upregulated TNF-α expression in the first 2 h, but this expression slowed down within 6-8 h, while IL-6 expression was increasing. This reduction was also observed for CXCL12/SDF1α. Unlike IL-10, IL-6 expression was constantly upregulated by prolonging incubation with LPS. TNF-α and CXCL12 gene expression occurred early in the time-course and exhibited a second increase following the first 4-6 h of incubation with LPS. Optimal expression of most adipokines needed 6-8 h of a prolonged treatment with LPS at 37 °C. The chemokines MIP-1α/CCL3 and MIP-1β/CCL4 were maximally expressed within the first 8 h, then significantly reduced in the following times. IL-10 expression was upregulated by low doses of LPS and downregulated by prolonging time with the bacterial endotoxin. ELISA analysis of released products generally confirmed the result from gene expression experiments. These data, while assessing previously reported results, highlighted new evidence about the time-dependency in LPS-mediated adipokine production, thus contributing to the comprehension of the inflammatory response of adipocyte.
    Full-text · Article · Feb 2014 · Agents and Actions
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    ABSTRACT: Endoplasmic reticulum (ER) stress is involved in the pathophysiology of atherosclerosis. Insults interfering with endoplasmic reticulum (ER) function, lead to accumulation of unfolded and misfolded proteins in ER that initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signaling is induced. We evaluated: 1) the UPR and ER-initiated apoptotic signaling in peripheral blood mononuclear cells (PBMC) of stable coronary artery disease patients (CAD); 2) PBMC content of oxidation products of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC); 3) the possible origin of oxPAPC in PBMC; 4) the expression of nuclear erytroid-related factor 2 (Nrf2)/antioxidant related element (ARE), a cellular defence mechanism. 29 CAD and 28 matched controls were enrolled. Expression of glucose-regulated protein 78kDa (GRP78/BiP) as representative of UPR, and of C/EBP homologous protein (CHOP) as representative of ER-apoptosis, were significantly higher in CAD than in controls (p<0.01). Concentrations of oxPAPC in PBMC, in plasma and in low density lipoprotein (LDL) resulted significantly higher in CAD than in controls (p<0.01). The oxPAPC in PBMC may derive from circulating ox-LDL. Nrf2/ARE gene expression and circulating and cellular glutathione (GSH) were significantly lower in CAD than in controls (p<0.01). In in vitro studies, increasing amounts of oxPAPC induced a dose-dependent increase of CHOP and apoptosis-related protein expression (p<0.01) and a progressive decrease of Nrf2/ARE gene expression (p<0.01). In PBMC of CAD patients there is an activation of UPR and of ER-initiated apoptotic signaling, possibly related to abnormal concentration of oxPAPC in PBMC.
    Full-text · Article · Dec 2013 · Free Radical Biology and Medicine
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    ABSTRACT: Although cigarette smoking has been associated with carotid intima-media thickness (CIMT) the mechanisms are yet not completely known. Lysophosphatidylcholine (lysoPC), a main product of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, appears to be a major determinant of the pro-atherogenic properties of oxidized LDL (oxLDL) and to induce proteoglycan synthesis, a main player in intimal thickening. In this study we assessed whether cigarette smoking-induced oxidative stress may influence plasma Lp-PLA2 and lysoPC and Lp-PLA2 expression in peripheral blood mononuclear cells (PBMC), as well as the relationship between lysoPC and CIMT.
    Full-text · Article · Dec 2013 · PLoS ONE
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    ABSTRACT: Purpose: The mechanisms underlying pathogenetic interactions between chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are largely unknown despite a clinical mutual association in causing mortality and morbidity. Besides smoking, obesity and systemic inflammation share the complicity of being causative factors for both CVD and COPD. The present study aims to investigate, in an unselected, community-dwelling, elderly population, possible relationships between lung and cardiovascular impairements. Methods: A screening questionnaire was administered to 500 subjects aged from 65 to 84 years, randomly selected from the general population of Verona. All consenting participants underwent conventional pulmonary function test and diagnostic cardiovascular study (Echocardiografy, carotid Echo-Color-Doppler and Ankle-Brachial-Index). Blood pressure (BP), body mass index (BMI) and biochemical metabolic blood data were routinely obtained from all the participants. Results: COPD vs not-COPD patients differ for age (mean age: 70 vs 67 ys) but not for BP (mean: 130/80 vs 130/82 mmHg), BMI (mean: 28 vs 27 g/m2), total cholesterol (mean: 192 vs 220 mg/dL) and glycaemia (mean: 102 vs 97 mg/dL). In COPD patient forced expiratory volume in the first second (FEV1) was linearly related to reductions in left ventricular end-diastolic volume (p<0.05) and stroke volume (p<0.05) but not with ejection fraction. Left ventricular mass is related to pO2 value (p<0.001). COPD patients related to control patients present: pathological Intima-Media-Thickness (mean: 0.12 vs 0.08 cm, p<0.001) and ABI (mean: 0.87 vs 1.05, p<0.001), a grater extension of atherosclerotic burden (mean number of carotid plague: 2.5 vs 1.2) and higher level of plaque calcification. Conclusions: Magnitude of changes in the cardiac structure and function is related to the severity of COPD. COPD patients show a great prevalence of peripheral vasculopathy and a typical pattern of cardiac and vascular remodelling that expose them to high cardiovascular risk. In particular the mechanical reduction of cardiac outflow linked to hyperinflation state, vascular tone regulation and stiffness due to O2 blood pressure variation and the great atherosclerotic tendency have to be taken into account in the evaluation of COPD patients.
    Preview · Article · Aug 2013 · European Heart Journal
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    ABSTRACT: Purpose: This study evaluated the incremental value and cost-effectiveness ratio of introducing coronary angiography (CA) with multidetector computed tomography (MDCT-CA) in the diagnostic management of patients with suspected coronary artery disease (CAD) compared with the traditional diagnostic workup. Material and methods: Five hundred and fifty consecutive patients who underwent MDCT-CA between January 2009 and June 2011 were considered. Patients with atypical chest pain and suspected obstructive CAD were directed to one of two diagnostic pathways: the traditional protocol (examination, stress test, CA) and the current protocol (examination, stress test, MDCT-CA, and CA, if necessary). The costs of each protocol and for the individual method were calculated. Based on the results, the cost-effectiveness ratio of the two diagnostic pathways was compared. A third, modified, diagnostic pathway has been proposed with its relative cost-effectiveness ratio (examination, MDCT-CA, stress test, and CA, if necessary). Results: Stress test vs. MDCT-CA had an accuracy of 66%, a sensitivity and specificity of 21% and 87%, respectively, and a positive (PPV) and negative (NPV) predictive value of 40% and 70%, respectively. Comparison between conventional CA (CCA) and MDCT-CA showed a sensitivity and specificity of 92% and 89%, respectively, a PPV and NPV of 89%, and an accuracy of 92%. The traditional protocol has higher costs than the second protocol: 1,645 euro against 322 euro (mean), but it shows a better cost-effectiveness ratio. The new proposed protocol has lower costs, mean 261 euro, with a better costeffectiveness ratio than the traditional protocol. Conclusions: The diagnostic protocol for patients with suspected CAD has been modified by the introduction of MDCT-CA. Our study confirms the greater diagnostic performance of MDCT-CA compared with stress test and its similar accuracy to CCA. The use of MDCT-CA to select patients for CCA has a favourable cost-effectiveness profile.
    No preview · Article · May 2013 · La radiologia medica
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    ABSTRACT: In recent years, evidence has emerged indicating that insulin resistance and diabetes mellitus type 2 are associated with inflammation of adipose tissue (AT). Interest has been focused on epicardial AT (EAT) because of its possible involvement with atherosclerosis and cardiovascular diseases. The aim of this study was to characterize adipocyte size and inflammatory profile in subcutaneous (SAT) and EAT among subjects with or without diabetes. Biopsies were collected from SAT and EAT in 34 men undergoing elective cardiac surgery. Weight, height, body mass index, waist circumference, as well as serum levels of glucose, insulin, lipids, adiponectin, and leptin were determined in all subjects. Adiponectin, MCP-1, and CD68 mRNA levels present within cells from AT biopsies were determined by real-time polymerase chain reaction. Adipocyte size was determined by optic microscopy and morphometry. Regarding the experimental group as a whole, gene-expression levels within EAT were significantly lower for adiponectin and higher, albeit not significantly, for MCP-1, when compared with that of SAT. In addition, adipocytes in EAT were significantly smaller than those in SAT. Subjects with diabetes showed lower adiponectin gene-expression levels in both SAT and EAT when compared with subjects without diabetes. By contrast, MCP-1 and CD68 gene-expression levels were higher in both tissue types of diabetic subjects. Adipocyte size in EAT was significantly larger in diabetic subjects than in nondiabetic subjects. Our data revealed a predominantly inflammatory profile in both SAT and EAT in subjects with diabetes in comparison with those without diabetes.
    No preview · Article · Jan 2013 · Heart and Vessels
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    ABSTRACT: Aims Expansion of necrotic core (NC), a major feature responsible for plaque disruption, is likely the consequence of accelerated macrophage apoptosis coupled with defective phagocytic clearance (efferocytosis). The cleavage of the extracellular domain of Mer tyrosine kinase (Mertk) by metallopeptidase domain17 (Adam17) has been shown to produce a soluble Mertk protein (sMer), which can inhibit efferocytosis. Herein, we analysed the expression and localization of Mertk and Adam17 in the tissue around the necrotic core (TANC) and in the periphery (P) of human carotid plaques. Then we studied the mechanisms of NC expansion by evaluating which components of TANC induce Adam17 and the related cleavage of the extracellular domain of Mertk.Methods and resultsWe studied 97 human carotid plaques. The expression of Mertk and Adam17 was found to be higher in TANC than in P (P < 0.001). By immunohistochemistry, Mertk was higher than Adam17 in the area of TANC near to the lumen (P < 0.01) but much lower in the area close to NC (P < 0.01). The extract of this portion of TANC increased the expression (mRNA) of Adam17 and Mertk (P < 0.01) in macrophage-like THP-1 cells but it also induced the cleavage of the extracellular domain of Mertk, generating sMer in the medium (P < 0.01). This effect of TANC extract was most evoked by its content in F 2-isoprostanes, hydroxyoctadecadienoic acids, and hydroxytetraenoic acids.Conclusion Some oxidized derivatives of polyunsaturated fatty acids contained in TANC of human carotid plaques are strong inducers of Adam17, which in turn leads to the generation of sMer, which can inhibit efferocytosis. © 2012 Published on behalf of the European Society of Cardiology. All rights reserved.
    Full-text · Article · Sep 2012 · Cardiovascular Research
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    ABSTRACT: Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), of nuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSH concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs). 52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokers we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and in peripheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showed impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs exposed to smokers' serum but not to non-smokers' serum we found that oxidative stress increased, whereas nitric oxide and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamate-cysteine ligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in smokers' serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant reduction of HO-1 and GCLC expression induced by oxPAPC in ECs. In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ARE pathway leading to GSH depletion.
    Full-text · Article · Jan 2012 · PLoS ONE

Publication Stats

3k Citations
607.62 Total Impact Points

Institutions

  • 1978-2015
    • University of Verona
      • • Department of Medicine
      • • Section of Internal Medicine
      • • Department of Biomedical and Surgical Sciences
      Verona, Veneto, Italy
  • 1980-2014
    • University of Padova
      • Department of Medicine DIMED
      Padua, Veneto, Italy
  • 2013
    • Azienda Ospedaliera Universitaria Integrata Verona
      • Division of Internal Medicine
      Verona, Veneto, Italy