Publications by authors named "Simona Bartimoccia"

51 Publications

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Int J Mol Sci 2021 Jul 3;22(13). Epub 2021 Jul 3.

I Clinica Medica, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy.

Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 ( < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22137193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267646PMC
July 2021

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Thorax 2021 06 19;76(6):618-620. Epub 2021 Apr 19.

IRCCS NeuroMed, Pozzilli, Italy.

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2020-215900DOI Listing
June 2021

Corticosteroid use, myocardial injury and in-hospital cardiovascular events in patients with community-acquired pneumonia.

Br J Clin Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Mediterranea Cardiocentro, Naples, Italy.

Background And Purpose: Corticosteroids are often prescribed to community-acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear.

Experimental Approach: 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High-sensitivity troponin T (hs-cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long-term follow-up.

Key Results: Overall, 318 patients (59%) showed hs-cTnT elevation >99th percentile (>0.014 μg/L). Age, heart failure and the increasing quintiles of hs-cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82-2.58, P < .001) predicted MACEs. Among patients with hs-cTnT >0.014 μg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs-cTnT increase (P = .021), (NADPH) oxidase-2 (Nox2) activation (P = .005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41-0.97, P = .038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity.

Conclusion And Implications: The study provides evidence that corticosteroid use is associated with lower increase of hs-cTnT and incidence of MACEs in CAP patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14936DOI Listing
June 2021

Chocolate enriched by extra virgin olive oil improves endothelial function and oxidative stress in patients with diabetes.

Nutrition 2021 Apr 7;90:111270. Epub 2021 Apr 7.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Mediterranea Cardiocentro, Napoli, Italy. Electronic address:

Objective: Endothelial dysfunction and oxidative stress are among the most relevant mechanisms underlying the atherosclerotic process in patients with type 2 diabetes mellitus (T2 DM). Extra virgin olive oil (EVOO) reduces postprandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation in healthy subjects and in patients with impaired fasting glucose. The aim of this study was to evaluate if the intake of chocolate enriched by EVOO had positive effects on endothelial function and oxidative stress in patients with T2 DM.

Methods: In this study we enrolled and randomly assigned 25 consecutive patients with T2 DM to receive 40 g of EVOO-enriched chocolate or 40 g of control chocolate spread. Participants were assessed at baseline and 2 h after chocolate intake. Endothelial function was assessed by arterial brachial flow-mediated dilation (FMD); oxidative stress was evaluated by the measurement of serum nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (Nox2) levels, nitric oxide availability, and serum hydrogen peroxide breakdown activity (HBA).

Results: We observed a significant increase of FMD, nitric oxide (NO) availability, and HBA in the EVOO-enriched chocolate group (P < 0.001). Conversely, soluble Nox2-derived peptide (sNox2-dp) levels significantly decreased (P < 0.001). No significant change was observed in the control chocolate group. To assess the relation of EVOO-enriched chocolate to endothelial function and oxidative stress, a general linear model (GLM) analysis was performed; a significant difference for treatments was found with respect to FMD, NO availability, HBA, and sNox-dp.

Conclusions: Administration of 40 g of EVOO-enriched chocolate is associated with increased endothelial function and reduction of oxidative stress in patients with T2 DM. Future studies are needed to analyze the effect of chronic assumption of EVOO-enriched chocolate on vascular function, oxidative stress, and cardiovascular complications in patients with T2 DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nut.2021.111270DOI Listing
April 2021

The Role of Antioxidants Supplementation in Clinical Practice: Focus on Cardiovascular Risk Factors.

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Faculty of Medicine and Surgery, Sapienza University of Rome, 04100 Latina, Italy.

Oxidative stress may be defined as an imbalance between reactive oxygen species (ROS) and the antioxidant system to counteract or detoxify these potentially damaging molecules. This phenomenon is a common feature of many human disorders, such as cardiovascular disease. Many of the risk factors, including smoking, hypertension, hypercholesterolemia, diabetes, and obesity, are associated with an increased risk of developing cardiovascular disease, involving an elevated oxidative stress burden (either due to enhanced ROS production or decreased antioxidant protection). There are many therapeutic options to treat oxidative stress-associated cardiovascular diseases. Numerous studies have focused on the utility of antioxidant supplementation. However, whether antioxidant supplementation has any preventive and/or therapeutic value in cardiovascular pathology is still a matter of debate. In this review, we provide a detailed description of oxidative stress biomarkers in several cardiovascular risk factors. We also discuss the clinical implications of the supplementation with several classes of antioxidants, and their potential role for protecting against cardiovascular risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox10020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909411PMC
January 2021

Poor Adherence to Mediterranean Diet and Serum Lipopolysaccharide are Associated with Oxidative Stress in Patients with Non-Alcoholic Fatty Liver Disease.

Nutrients 2020 Jun 10;12(6). Epub 2020 Jun 10.

I Clinica Medica, Department of Clinical Internal, Anestesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome 00185, Italy.

Oxidative stress plays a pivotal role in non-alcoholic fatty liver disease (NAFLD). Factors inducing oxidative stress in NAFLD may be several; however, a relationship with the adherence to Mediterranean Diet (Med-diet) and with serum lipopolysaccharide (LPS) has been poorly investigated in this setting. The aim was to investigate factors associated with impaired oxidative stress in NAFLD, focusing on the potential role of LPS and Med-diet. We enrolled 238 consecutive outpatients from the PLINIO study, in whom we measured the soluble Nox2-derived peptide (sNox2-dp), a marker of systemic oxidative stress, and serum LPS. Adherence to Med-diet was investigated by a nine-item validated dietary questionnaire. Serum sNox2-dp and LPS were higher in patients with NAFLD compared to those without (25.0 vs. 9.0 pg/mL, < 0.001 and 62.0 vs. 44.9 pg/mL, < 0.001, respectively). In patients with NAFLD, the highest sNox2-dp tertile was associated with the top serum LPS tertile (Odds Ratio (OR): 4.71; p < 0.001), APRI > 0.7 (OR: 6.96; p = 0.005) and Med-diet-score > 6 (OR: 0.14; p = 0.026). Analyzing individual foods, the daily consumption of wine (OR: 0.29, = 0.046) and the adequate weekly consumption of fish (OR: 0.32, = 0.030) inversely correlated with the top sNox2-dp tertile. In conclusion, patients with NAFLD showed impaired oxidative stress. Levels of sNox2 correlated with serum LPS and with low adherence to Med-Diet.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12061732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352324PMC
June 2020

Is There an Association Between Atherosclerotic Burden, Oxidative Stress, and Gut-Derived Lipopolysaccharides?

Antioxid Redox Signal 2020 May 18. Epub 2020 May 18.

Division I Medical Clinic, Department of Clinical, Internistic, Anaesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Recent studies hypothesized a role of gut microbiota favoring atherosclerosis an increased oxidative stress, but data in peripheral artery disease (PAD) have not been provided yet. The aim of this study was to assess serum lipopolysaccharide (LPS) as well as oxidative stress in PAD patients and controls (CT). Furthermore, we wanted to analyze the relationship between LPS and the severity of atherosclerosis in the lower limb arteries. Eighty consecutive subjects, including 40 PAD patients and 40 CT were recruited. A cross-sectional study was performed to compare serum LPS, soluble Nox2-derived peptide (sNox2-dp), hydrogen peroxide (HO), HO breakdown activity (HBA) and ankle brachial index (ABI) in these two groups. Serum zonulin was used to assess gut permeability. Compared with CT, PAD patients had significant higher values of LPS, zonulin, sNox2-dp, and HO; conversely ABI and HBA were significantly lower in PAD patients. LPS serum levels were associated with atherosclerotic burden as depicted by the inverse correlation with ABI. LPS was also associated with oxidative stress as shown by its direct correlation with markers of oxidative stress such as sNox2-dp, serum HO, and HBA. Finally, we found a significant correlation between LPS and zonulin. A multiple linear regression analysis showed that LPS was significantly associated only with ABI. These findings suggest that LPS is elevated in PAD patients with a close association with the atherosclerotic burden and oxidative stress. The correlation between LPS and zonulin suggests that changes in gut permeability could be a potential trigger of LPS translocation in the peripheral circulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2020.8109DOI Listing
May 2020

A novel role of MMP2 in regulating platelet NOX2 activation.

Free Radic Biol Med 2020 05 5;152:355-362. Epub 2020 Apr 5.

Mediterranea, Cardiocentro, 80122, Napoli, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100, Latina, Italy. Electronic address:

NOX2 has a key role for cellular production of reactive oxidant species (ROS) and although the mechanism of its activation is well known, little is known about its regulation. Metallo-proteinases (MMPs) regulate numerous protein activities both in physiological and pathological conditions but their interplay with NOX2 and ROS formation is still unclear. We performed experimental studies in human platelets and polymorphonuclear leukocytes (PMNs) to investigate the interplay of MMP2 with NOX2 activity. In collagen-stimulated platelets and in PMA-stimulated PMNs from healthy subjects, an immediate burst of ROS was detected at 10 min to then decline at 20 min. Coincidentally, sNOX2-dp, a split-off product of NOX2, increased and peaked at 10 min. ROS production was persistent whereas sNOX2dp is not released in cells treated with MMP2 inhibitor compared to other MMPs inhibitors. Western blot analysis showed the highest MMP2 expression on the cell membrane 10 min after stimulation. Moreover, the co-immunoprecipitation assay confirms the interaction between MMP2 and NOX2 that formed an active immuno-complex. Treating cells with NOX2ds-tat, an inhibitor of NADPH oxidase, significantly reduced ROS formation, sNOX2-dp, MMP2 expression and MMP2-NOX2-complex, which were all restored if cells were added with HO. The study provides the first evidence that MMP2 has a key role in blunting platelet NOX2 activity and eventually ROS formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2020.03.033DOI Listing
May 2020

PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation.

Antioxidants (Basel) 2020 Apr 2;9(4). Epub 2020 Apr 2.

Mediterranea Cardiocentro, 80122 Naples, Italy.

Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA).

Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2) formation and soluble P-selectin levels as markers of PA and soluble Nox2-derived peptide (sNox2-dp), HO, isoprostanes and oxidized Low-Density-Lipoprotein (oxLDL) to analyze oxidative stress (OS) in 88 patients having PCSK9 values < ( = 44) or > ( = 44) 1.2 ng/mL, balanced for age, sex and cardiovascular risk factors. Furthermore, we investigated if normal ( = 5) platelets incubated with PCSK9 (1.0-2.0 ng/mL) alone or with LDL (50 µg/mL) displayed changes of PA, OS and down-stream signaling.

Results: PA and OS markers were significantly higher in patients with PCSK9 levels > 1.2 ng/mL compared to those with values < 1.2 ng/mL ( < 0.001). Levels of PCSK9 significantly correlated with markers of PA and OS. Platelets incubation with PCSK9 increased PA, OS and p38, p47 and Phospholipase A2 (PLA2) phosphorylation. These changes were amplified by adding LDL and blunted by CD36 or Nox2 inhibitors. Co-immunoprecipitation analysis revealed an immune complex of PCSK9 with CD36.

Conclusions: We provide the first evidence that PCSK9, at concentration found in the circulation of AF patients, directly interacts with platelets via CD36 receptor and activating Nox2: this effect is amplified in presence of LDL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox9040296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222182PMC
April 2020

Oleuropein-enriched chocolate by extra virgin olive oil blunts hyperglycaemia in diabetic patients: Results from a one-time 2-hour post-prandial cross over study.

Clin Nutr 2020 07 21;39(7):2187-2191. Epub 2019 Sep 21.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Mediterranea, Cardiocentro-Napoli, Italy. Electronic address:

Background & Aims: Oleuropein, a component of extra virgin olive oil (EVOO), reduces post-prandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation. In this study we evaluated if the intake of an oleuropein-enriched chocolate could have positive effects on glycaemia and insulin levels in patients with type 2 diabetes mellitus (T2DM) and healthy subjects (HS).

Methods: Twenty-five consecutive T2DM patients and 20 HS were recruited. Participants were randomized to receive 40 g oleuropein-enriched chocolate by EVOO or 40 g control chocolate spread in a cross-over design. Serum glucose, insulin, glucagon-like peptide-1 (GLP1), and dipeptidyl-peptidase-4 (DPP4) were measured before and 2 h after chocolate intake.

Results: In T2DM, the pairwise comparisons showed that intake of oleuropein-enriched chocolate was associated with a significantly less increase of blood glucose compared to control; GLM analysis showed a significant difference for treatments with respect to glucose (p = 0.04), GLP1 (p < 0.001) and DPP-4 activity (p = 0.01). In HS, the pairwise comparisons showed that, after oleuropein-enriched chocolate intake, blood glucose concentration and DPP4 activity did not change; conversely a significant increase was observed for insulin and GLP1. After control chocolate intake, a significant increase for blood glucose, insulin levels and DPP4 activity were observed while GLP1 did not change.

Conclusion: The study shows that using EVOO as source of oleuropein administration of 40 g oleuropein-enriched chocolate is associated with a modest increase or no change of glycemia in T2DM and HS respectively, via an incretin-mediated mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2019.09.006DOI Listing
July 2020

Interaction between serum endotoxemia and proprotein convertase subtilisin/kexin 9 (PCSK9) in patients with atrial fibrillation: A post-hoc analysis from the ATHERO-AF cohort.

Atherosclerosis 2019 10 4;289:195-200. Epub 2019 Jul 4.

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy; Mediterranea Cardiocentro, Napoli, 80122, Italy. Electronic address:

Background And Aims: Lipopolysaccharides (LPS) is emerging as a novel risk factor for cardiovascular events (CVEs). Furthermore, in vitro evidence suggested that LPS may elicit proprotein convertase subtilisin/kexin 9 (PCSK9) expression, but their relationship in vivo has not been investigated.

Methods: We conducted a post-hoc analysis of a prospective, single centre cohort study of 907 patients with non-valvular atrial fibrillation (AF). At baseline, PCSK9, LPS and NADPH oxidase (sNox2-dp) were measured. PCSK9 and LPS were correlated with the incidence of CVEs.

Results: Median PCSK9 and LPS were 1200 [900-1970] and 49.9 [15.0-108.2] pg/ml, respectively. LPS and PCSK9 were significantly correlated (rS 0.378, p < 0.001). Logistic regression analysis showed that LPS was associated with PCSK9 above the median (odds ratio [OR] 1.727 95% confidence interval [CI] 1.147-2.600 p = 0.009). Other factors associated with PCSK9 above the median were sNox2-dp (OR 1.759 C.I. 95% 1.167-2.650, p = 0.007), use of antiplatelet drugs (OR 0.437 95%CI 0.219-0.871 p = 0.017) and high adherence to Mediterranean diet (OR 0.737 95%CI 0.643-0.845 p = 0.001). Olive oil (OR 0.376 95%CI 0.185-0.763, p = 0.001) and wine (OR 0.460 95%CI 0.289-0.733 p = 0.007) were negatively associated with PCSK9. Patients with concomitant high PCSK9 and LPS (LPS ≥88 pg/ml and PCSK9 ≥1570 pg/ml) had an increased risk of CVEs compared to those with low levels (LPS <24.3 pg/ml and PCSK9 <1000 pg/ml, Log-Rank test, p = 0.022).

Conclusions: This study demonstrated, for the first time in vivo, that circulating levels of PCSK9 and LPS are associated with a mechanism possibly involving NADPH oxidase activation. Patients with concomitant increase of PCSK9 and LPS showed a higher risk of CVEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.002DOI Listing
October 2019

Does the Coexistence of Chronic Obstructive Pulmonary Disease and Atrial Fibrillation Affect Nox2 Activity and Urinary Isoprostanes Excretion?

Antioxid Redox Signal 2019 10 23;31(11):786-790. Epub 2019 Jul 23.

Department of Internal Medicine and Medical Specialties, I Clinica Medica, Atherothrombosis Centre, Sapienza University, Rome, Italy.

Chronic obstructive pulmonary disease (COPD) and atrial fibrillation (AF) are characterized by increased oxidative stress, but the impact of the coexistence of COPD and AF on systemic oxidative stress is unclear. We performed a cross-sectional study including 157 outpatients to investigate the Nox2-related oxidative stress in patients with AF and COPD. COPD was defined by an FEV/FVC <0.70. Oxidative stress was measured by sNox2-dp, a marker of Nox2 activation, and urinary isoprostanes. We divided patients into four groups: Group 0: hypertension ( = 49, controls); Group 1: COPD ( = 42); Group 2: AF ( = 33); and Group 3: COPD and AF ( = 33). Mean age was 68.3 ± 11.0 years, and 46.5% were women. Patients with COPD or AF showed increased levels of sNox2-dp as compared with group 0; sNox2-dp further increased in patients with COPD + AF. In these patients, sNox2-dp was higher than in those with COPD ( < 0.001) or AF ( = 0.003). At multivariable logistic regression analysis, chronic kidney disease, COPD, and AF were associated with sNox2-dp above median. Similar results were observed for urinary isoprostanes. We hypothesize that the coexistence of COPD in AF patients may be associated with an increased systemic oxidative stress by the upregulation of Nox2. 31, 786-790.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2019.7811DOI Listing
October 2019

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis.

Hepatol Commun 2019 Apr 2;3(4):504-512. Epub 2019 Mar 2.

Department of Internal Medicine and Medical Specialties Sapienza University of Rome Rome Italy.

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the study and 4 healthy subjects (HSs) were entered in the study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; = 0.012) and serum albumin (OR, -0.422; = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand ( = 0.0238), soluble Nox2-derived peptide (sNox2-dp; < 0.0001), and urinary excretion of isoprostanes ( = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD40L (Spearman's rank correlation coefficient [ ], -0.33; < 0.001), sNox2-dp ( , -0.57; < 0.0001), and urinary excretion of isoprostanes ( -0.48; < 0.0001) levels. The study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2α-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442692PMC
April 2019

Nox2-mediated platelet activation by glycoprotein (GP) VI: Effect of rivaroxaban alone and in combination with aspirin.

Biochem Pharmacol 2019 05 13;163:111-118. Epub 2019 Feb 13.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Mediterranea, Cardiocentro-Napoli, Italy. Electronic address:

Factor Xa (FXa) has been reported to activate platelet via interaction with glycoprotein (GP) VI but the underlying mechanism has not been fully elucidated. We investigated if Nox2-derived oxidative stress is implicated in FXa-induced platelet aggregation (PA), and the effect of a FXa inhibitor, namely rivaroxaban, with or without aspirin (ASA), on PA. We performed an in vitro study measuring convulxin-induced PA, thromboxane (Tx) B and isoprostanes biosynthesis, soluble Nox2-dp (sNox2-dp), a marker of Nox2 activation, soluble GPVI (sGPVI) and PLA activation in platelets from healthy subjects (n = 5) added with and without a Nox2 inhibitor. The same variables were also examined in platelets treated with rivaroxaban (15-60 ng/ml), combined or less with ASA (25 µM). Convulxin-stimulated platelets increased sGPVI, sNox2-dp, HO, eicosanoid biosynthesis and PLA phosphorylation, which were all inhibited by a Nox2 inhibitor. Rivaroxaban alone significantly reduced PA, sGPVI, TxB and isoprostanes biosynthesis, concomitantly with Syk, sNox2-dp and PLA activation in a dose-dependent fashion; a significant effect was achieved with 30 ng/ml rivaroxaban. Docking simulation analysis showed that rivaroxaban interacts with GPVI. In platelets co-incubated with ASA, rivaroxaban amplified the ASA antiplatelet effect, which was achieved with 30 ng/ml and prevalently attributable to Nox2 inhibition and impaired isoprostane biosynthesis. Here we show that rivaroxaban, at concentrations achievable in human circulation, inhibits PA via GPVI interaction and eventually Nox2-mediated isoprostanes biosynthesis and amplifies the ASA antiplatelet effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2019.02.016DOI Listing
May 2019

Digoxin and Platelet Activation in Patients With Atrial Fibrillation: In Vivo and In Vitro Study.

J Am Heart Assoc 2018 11;7(22):e009509

1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy.

Background Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation ( AF ). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Methods and Results Post hoc analysis of a prospective study of anticoagulated patients with AF . Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11-dehydro-thromboxane B (TxB), a marker of platelet activation, and serum digoxin concentration ( SDC ) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6-2.4 ng/mL) with or without prestimulation with a sub-threshold of collagen. Median 11-dehydro-TxB was 105.0 ( interquartile range, 60.0-190.0) ng/mg creatinine, and median SDC was 0.65 ( interquartile range, 0.40-1.00) ng/mL. Urinary 11-dehydro-TxB and SDC were correlated ( r=0.350, P<0.001). Patients in the upper tertile of SDC showed higher 11-dehydro-TxB compared with non-digoxin users ( P=0.019). In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects . Digoxin (2.4 ng/mL) induced calcium mobilization, PAC -1 (procaspase-activating compound 1) and platelet aggregation in AF patients but not in healthy subjects . After pretreatment with a sub-threshold of collagen, digoxin dose-dependent induced calcium mobilization, arachidonic acid release, TxB biosynthesis, PAC -1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin. Conclusions We found a significant in vivo correlation between SDC and platelet activation. Supratherapeutic SDC increased in vitro platelet aggregation via calcium-related phospholipase A phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.118.009509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404445PMC
November 2018

Interplay between Oxidative Stress and Platelet Activation in Coronary Thrombus of STEMI Patients.

Antioxidants (Basel) 2018 Jul 3;7(7). Epub 2018 Jul 3.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, 00161 Rome, Italy.

Background: Platelet activation and oxidative stress seem to play a key role in coronary thrombus formation and are associated with thrombus burden in ST-elevation myocardial infarction (STEMI). However, the interplay between oxidative stress and platelet activation has not been fully elucidated.

Materials And Methods: For 32 patients with STEMI undergoing primary percutaneous coronary intervention (PPCI) and 10 patients with stable angina (SA) and oxidative stress, as assessed by NADPH isoform 2 activity (soluble Nox2-derived peptide, sNox2-dp), levels of oxidized low-density lipoproteins (oxLDLs) and platelet activation markers such as soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were measured in the retrieved material (coronary thrombi plus blood waste) of STEMI patients and in intracoronary blood of SA patients, respectively, and in peripheral blood samples of both groups.

Results: In aspirated thrombi and blood waste of STEMI patients we found higher serum levels of sNox2-dp, oxLDLs, sCD40L, and sP-selectin, as compared to the intracoronary blood samples of SA patients. Moreover, in thrombi and blood waste of STEMI patients, a direct correlation between markers of oxidative stress and of platelet activation was found. Also, in STEMI patients a progressive increase of oxidative stress and platelet activation markers was observed according to the thrombus score burden. STEMI patients showed higher peripheral blood Nox2 activity and oxLDL levels as compared to SA patients.

Conclusion: This study shows a close relationship between oxidative stress and platelet activation in the intracoronary blood waste and aspirated thrombi of STEMI patients, suggesting a role of oxidative stress in promoting thrombus formation and growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox7070083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070897PMC
July 2018

Antioxidant activity from extra virgin olive oil via inhibition of hydrogen peroxide-mediated NADPH-oxidase 2 activation.

Nutrition 2018 11 29;55-56:36-40. Epub 2018 Mar 29.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Objectives: Extra virgin olive oil (EVOO) supplementation is associated with a significant reduction in cardiovascular disease but the underlying mechanism is still unclear.

Methods: In platelets that were taken from healthy subjects (n = 5), agonist-induced hydrogen peroxide (HO) production and NADPH oxidase 2 (NOX2) activation in the presence of or without catalase, which catabolizes HO, were investigated. Platelet HO production, NOX2 activation, EVOO vitamin E, and total polyphenols as well as EVOO's ability to scavenge HO were also measured.

Results: Platelet NOX2 activation and HO production were significantly inhibited in catalase-treated platelets and platelets that were incubated with five different EVOOs. The EVOO content of vitamin E was 53 to 223 mg/kg and total polyphenols 145 to 392 mg/L Gallic acid equivalent. EVOOs quenched in vitro HO by 39 to 62%, which is an effect that is significantly correlated with vitamin E and total polyphenol concentrations (R = 0.688; P <0.001 and R = 0.541; P <0.001, respectively).

Conclusions: This in vitro study provides the first evidence that EVOO downregulates platelet HO and in turn NOX2 activity via HO scavenging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nut.2018.03.045DOI Listing
November 2018

Gut-derived lipopolysaccharides increase post-prandial oxidative stress via Nox2 activation in patients with impaired fasting glucose tolerance: effect of extra-virgin olive oil.

Eur J Nutr 2019 Mar 16;58(2):843-851. Epub 2018 May 16.

I Clinica Medica, Atherothrombosis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Purpose: Post-prandial phase is characterized by enhanced oxidative stress but the underlying mechanism is unclear. We investigated if gut-derived lipopolysaccharide (LPS) is implicated in this phenomenon and the effect of extra virgin olive oil (EVOO) in patients with impaired fasting glucose (IFG).

Methods: This is a randomized cross-over interventional study including 30 IFG patients, to receive a lunch with or without 10 g of EVOO. Serum LPS, Apo-B48, markers of oxidative stress such as oxidized LDL (oxLDL) and soluble Nox2-derived peptide (sNox2-dp), a marker of nicotinamide-adenine-dinucleotide-phosphate oxidase isoform Nox2 activation, and plasma polyphenols were determined before, 60 and 120 min after lunch.

Results: In patients not given EVOO oxidative stress as assessed by sNox2-dp and oxLDL significantly increased at 60 and 120 min concomitantly with an increase of LPS and Apo-B48. In these patients, changes of LPS were correlated with Apo-B48 (Rs = 0.542, p = 0.002) and oxLDL (Rs = 0.463, p = 0.010). At 120 min, LPS (β - 15.73, p < 0.001), Apo-B48 (β - 0.14, p = 0.004), sNox2-dp (β - 5.47, p = 0.030), and oxLDL (β - 42.80, p < 0.001) significantly differed between the two treatment groups. An inverse correlation was detected between polyphenols and oxLDL (R - 0.474, p < 0.005). In vitro study showed that LPS, at the same concentrations found in the human circulation, up-regulated Nox2-derived oxidative stress via interaction with Toll-like receptor 4.

Conclusions: Post-prandial phase is characterized by an oxidative stress-related inflammation potentially triggered by LPS, a phenomenon mitigated by EVOO administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00394-018-1718-xDOI Listing
March 2019

Blood hydrogen peroxide break-down activity in healthy subjects and in patients at risk of cardiovascular events.

Atherosclerosis 2018 07 25;274:29-34. Epub 2018 Apr 25.

I Clinica Medica, Atherothrombosis Centre, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy.

Background And Aims: Antioxidant status has been shown to be associated with cardiovascular events (CVEs). The aim of the study was to develop an assay measuring serum hydrogen peroxide (HO) break-down activity (HBA) of healthy subjects (HS) and to validate it in a cohort of patients with atrial fibrillation (AF).

Methods: We developed the HBA assay in 121 HS and validated it in 842 AF patients. The occurrence of CVEs was registered and correlated with HBA in AF during a median follow-up of 30.6 months (3226 patient-years). A combined endpoint of CVEs included fatal/non-fatal ischemic stroke and myocardial infarction, cardiovascular death and transient ischemic attack.

Results: In HS, median HBA was 61.2% [IQR: 52.9-69.4]. AF patients disclosed lower HBA than 30 HS balanced for age and sex (48.6% [IQR: 24.7-65.1] vs. 59.4% [IQR: 49.2-66.2], p < 0.001). During a mean follow-up of 30.6 months (3226 patient-years), 168 CVEs occurred (5.2%/year). A multivariable Cox's proportional hazards regression analysis showed that age group 3 (71-80 years, HR:5.419, p = 0.020), age group 4 (>80 years, HR:9.783, p = 0.002), diabetes (HR:1.464, p = 0.049), previous cardiac events (HR:1.887, p = 0.001) and HBA (below median, HR:2.313, p < 0.001) predicted CVEs.

Conclusions: We developed an easy assay to measure serum HBA, which was associated with CVEs in AF patients. This assay may represent an additional useful tool for cardiovascular risk stratification and should be validated in other high-risk populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2018.04.025DOI Listing
July 2018

Oleuropein, a component of extra virgin olive oil, lowers postprandial glycaemia in healthy subjects.

Br J Clin Pharmacol 2018 07 2;84(7):1566-1574. Epub 2018 May 2.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Aims: Extra virgin olive oil lowers postprandial glycaemia. We investigated if oleuropein, a component of extra virgin olive oil, exerts a similar effect on postprandial glycaemia and the underlying mechanism.

Methods: Twenty healthy subjects were randomly allocated in a cross-over design to 20 mg oleuropein or placebo immediately before lunch. Postprandial glycaemia along with blood insulin, dipeptidyl-peptidase-4 (DPP-4) and glucagon-like peptide-1 and oxidative stress, which included soluble NADPH oxidase-derived peptide activity (sNox2-dp), 8-iso-prostaglandin-2α and platelet p47 phosphorylation, were analysed before and 2 h after meal.

Results: After 2 h, subjects who assumed oleuropein had significantly lower blood glucose, DPP-4 activity and higher insulin and glucagon-like peptide-1 compared to placebo. Furthermore, sNox2-dp, 8-iso-PGF2α and platelet p47 phosphorylation were significantly lower in oleuropein- compared to placebo-treated subjects. DPP-4 significantly correlated with sNox2-dp [Spearman's rho (Rs) = 0.615; P < 0.001], p47 phosphorylation (Rs = 0.435; P < 0.05) and 8-iso- prostaglandin-2α (Rs = 0.33; P < 0.05). In vitro study demonstrated that hydroxytyrosol, a metabolite of oleuropein, significantly reduced p47 phosphorylation and isoprostane formation.

Conclusions: These findings indicate that oleuropein improves postprandial glycaemic profile via hampering Nox2-derived oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.13589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005585PMC
July 2018

Early decrease of oxidative stress by non-invasive ventilation in patients with acute respiratory failure.

Intern Emerg Med 2018 03 15;13(2):183-190. Epub 2017 Sep 15.

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Oxidative stress plays an important role in chronic respiratory diseases where the use of non-invasive ventilation seems to reduce the oxidative damage. Data on acute respiratory failure are still lacking. The aim of the study is to investigate the interplay between oxidative stress and acute respiratory failure, and the role of non-invasive ventilation in this setting. We enrolled 60 patients suffering from acute respiratory failure (PaO/FiO ratio <300): 30 consecutive patients treated with non-invasive ventilation and 30 consecutive patients treated with conventional oxygen therapy. Serum levels of soluble Nox2-derived peptide (sNOX2-dp), a marker of NADPH-oxidase activation, and 8-iso-PGF2α and HO, markers of oxidative stress, were evaluated at baseline and after 3 h of treatment. At baseline, higher values of sNOX2-dp, 8-iso-PGF2α and HO are associated with lower values of PaO/FiO ratio (p < 0.001). After 3 h, serum levels of sNOX2-dp, HO, and 8-iso-PGF2α significantly decrease in patients treated with non-invasive ventilation, but not in patients treated with conventional oxygen therapy. Delta changes of oxidative stress parameters correlate inversely with the delta changes of PaO/FiO (R = -0.623, p < 0.001 for sNOX2-dp; R = -0.428, p < 0.001 for HO; R = -0.548, p < 0.001 for 8-iso-PGF2α). In the acute respiratory failure setting, treatment with non-invasive ventilation reduces the levels of oxidative stress in the first hours. This reduction is associated with an improvement of PaO/FiO ratio as well as in a reduction of NADPH-oxidase activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11739-017-1750-5DOI Listing
March 2018

Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation.

J Am Coll Cardiol 2017 Sep;70(12):1455-1462

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available.

Objectives: This study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B (11-dh-TxB), a marker of platelet activation.

Methods: We conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient-years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB (n = 852) were measured. The population was divided into tertiles of PCSK9 for the analysis.

Results: The mean age of patients was 73.5 ± 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB were significantly correlated (Spearman's rho: 0.665; p < 0.001).

Conclusions: Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB suggests PCSK9 as a mechanism potentially implicated in platelet activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2017.07.743DOI Listing
September 2017

Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis.

J Hepatol 2017 11 14;67(5):950-956. Epub 2017 Jul 14.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. Electronic address:

Background & Aims: Patients with cirrhosis display enhanced blood levels of factor VIII, which may result in harmful activation of the clotting system; however, the underlying mechanism is unknown.

Methods: We performed a cross-sectional study in patients with cirrhosis (n=61) and matched controls (n=61) comparing blood levels of factor VIII, von Willebrand factor (vWf), lipopolysaccharide (LPS) and positivity for Escherichia coli DNA. Furthermore, we performed an in vitro study to investigate if LPS, in a concentration range similar to that found in the peripheral circulation of cirrhotic patients, was able to elicit factor VIII secretion from human umbilical vein endothelial cells (HUVEC).

Results: Patients with cirrhosis displayed higher serum levels of LPS (55.8 [42.2-79.9] vs. 23.0 [7.0-34.0]pg/ml, p<0.001), factor VIII (172.0 [130.0-278.0] vs. 39.0 [26.0-47.0]U/dl, p<0.0001), vWf (265.0 [185.0-366.0] vs. 57.0 [48.0-65.0]U/dl, p<0.001) and positivity for Escherichia coli DNA (88% vs. 3%, p<0.001, n=34) compared to controls. Serum LPS correlated significantly with factor VIII (r=0.80, p<0.001) and vWf (r=0.63, p<0.001). Only LPS (beta-coefficient=0.70, p<0.0001) independently predicted factor VIII levels. The in vitro study showed that LPS provoked factor VIII and vWf release from HUVEC via formation and secretion of Weibel-Palade bodies, a phenomenon blunted by pre-treating HUVEC with an inhibitor of Toll-like receptor 4.

Conclusions: The study provides the first evidence that LPS derived from gut microbiota increases the systemic levels of factor VIII via stimulating its release by endothelial cells. Lay summary: Cirrhosis is associated with thrombosis in portal and systemic circulation. Enhanced levels of factor VIII have been suggested to play a role but the underlying mechanism is still unclear. Here we show that patients with cirrhosis display a concomitant increase of factor VIII and lipopolysaccharide (LPS) from Escherichia coli and suggest that LPS contributes to the release of factor VIII from endothelial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2017.07.002DOI Listing
November 2017

Lipopolysaccharide as trigger of platelet aggregation via eicosanoid over-production.

Thromb Haemost 2017 07 11;117(8):1558-1570. Epub 2017 May 11.

Francesco Violi, Department of Internal Medicine and Medical Specialties, Viale del Policlinico 155, Rome, 00161, Italy, Tel.: +39 064461933, Fax: +39 0649970103, E-mail:

The effect of lipopolysaccharide (LPS) on platelet aggregation is still controversial. We performed in vitro and ex vivo studies in controls and in patients with community-acquired pneumonia (CAP) to assess the effect of LPS on platelet activation (PA). LPS (15-100 pg/ml) significantly increased PA only if combined with sub-threshold concentrations (STC) of collagen or ADP; this effect was associated with increased platelet HO production, Nox2 activation, PLA2 phosphorylation, thromboxane (Tx)A and 8-iso-PGF2α-III, and was inhibited by aspirin, TxA2 receptor antagonist or by Toll-like receptor 4 blocking peptide (TLR4bp). Analysis of up-stream signalling potentially responsible for Nox2 and PLA2 activation demonstrated that LPS-mediated PA was associated with phosphorylation of AKT, p38 and p47phox translocation. In 10 consecutive CAP patients serum endotoxins were significantly higher compared to 10 controls (145 [115-187] vs 18 [6-21] pg/ml; p<0.01). Ex vivo study showed that agonist-stimulated platelets were associated with enhanced PA (p<0.01), Toll-like receptor 4 (TLR4) expression (p<0.05), TxA (p<0.01) and 8-iso-PGF2α-III (p<0.01) production in CAP patients compared to controls. The study provides evidence that LPS amplifies the platelet response to common agonists via TLR4-mediated eicosanoid production and suggests LPS as a potential trigger for PA in CAP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH16-11-0857DOI Listing
July 2017

Is There an Interplay Between Adherence to Mediterranean Diet, Antioxidant Status, and Vascular Disease in Atrial Fibrillation Patients?

Antioxid Redox Signal 2016 11 30;25(14):751-755. Epub 2016 Sep 30.

1 Department of Internal Medicine and Medical Specialties, I Clinica Medica, Atherothrombosis Centre, Sapienza University of Rome , Rome, Italy .

Mediterranean Diet (Med-Diet) is associated with reduced incidence of vascular events (VEs) in atrial fibrillation (AF), but the mechanism accounting for its beneficial effect is only partially known. We hypothesized that Med-Diet may reduce VEs by improving antioxidant status, as assessed by glutathione peroxidase 3 (GPx3) and superoxide dismutase (SOD). We performed a prospective cohort study investigating the relationship between adherence to Med-Diet, serum baseline GPx3 and SOD activities, and the occurrence of VEs in 690 AF patients. GPx3 activity was directly associated with Med-Diet score (B = 0.192, p < 0.001) and inversely with age (B = -0.124, p = 0.001), after adjustment for potential confounders; Med-Diet weakly affected SOD levels. During a mean follow-up of 46.1 ± 28.2 months, 89 VEs were recorded; patients with VEs had lower GPx3 levels compared with those without VEs (p = 0.002); and no differences regarding SOD activity were found. Multivariable Cox regression analysis showed that age (Hazard ratio [HR]:1.065, p < 0.001), logGPx3 (above median, HR: 0.629, p < 0.05), and Med-Diet score (HR: 0.547, p < 0.05) predicted VEs. Med-Diet favorably modulates antioxidant activity of GPx3 in AF, resulting in reduced VEs rate. We hypothesize that the modulation of GPx3 levels by Med-Diet could represent an additional nutritional strategy to prevent VEs in AF patients. Antioxid. Redox Signal. 25, 751-755.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2016.6839DOI Listing
November 2016

Age-related increase of thromboxane B2 and risk of cardiovascular disease in atrial fibrillation.

Oncotarget 2016 Jun;7(26):39143-39147

I Clinica Medica, Atherothrombosis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Aging is strictly associated with an increased incidence of cardiovascular events (CVEs) in the general population. Mechanisms underlying the risk of CVEs are still unclear. Platelet activation contributes to the onset of cardiovascular complications. The incidence of atrial fibrillation (AF) increases with age, and the natural history of AF is often complicated by CVEs. We prospectively investigated the relationship between age, urinary thromboxane (Tx) B2, which reflects platelet activation, and CVEs in 833 AF patients. Median TxB2 level was 120 [66-200] ng/mg of urinary creatinine. At multivariable linear regression analysis, age (B: 0.097, p=0.005) and previous MI/CHD (B: 0.069, p=0.047) were associated with log-TxB2 levels. When we divided our population into age classes (i.e. < 60, 60-69, 70-79, ≥ 80 years), we found a significant difference in TxB2 levels across classes (p=0.005), with a significant elevation at 74.6 years. During a mean follow-up of 40.9 months, 128 CVEs occurred; the rate of CVEs significantly increased with age classes (Log-rank test, p < 0.001). TxB2 levels were higher in patients with, compared to those without, CVEs in patients aged 70-79 (p < 0.001) and ≥ 80 (p = 0.020) years. In conclusion, TxB2 levels enhance by increasing age, suggesting that platelet activation contributes to CVEs in elderly patients with AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.9826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129920PMC
June 2016

Anti Xa oral anticoagulants inhibit in vivo platelet activation by modulating glycoprotein VI shedding.

Pharmacol Res 2016 11 28;113(Pt A):484-489. Epub 2016 Sep 28.

IClinica Medica, Atherothrombosis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy.

Anti Xa non-vitamin K oral anticoagulants (anti Xa NOACs) seem to possess antiplatelet effect in vitro, but it is unclear if this occurs also in vivo. Aim of the study was to compare the effect on platelet activation of two anti Xa NOACs, namely apixaban and rivaroxaban, to warfarin, and to investigate the potential underlying mechanism by evaluating soluble glycoprotein GPVI (sGPVI), a protein involved in platelet activation. We performed a cross-sectional including AF patients treated with warfarin (n=30), or apixaban 10mg/day (n=40), or rivaroxaban 20mg/day (n=40). Patients were balanced for sex, age and cardiovascular risk factors. Platelet activation by urinary excretion of 11-dehydro-thromboxane (Tx) B and soluble GPVI (sGPVI) were analysed at baseline and after 3 months of treatment. Baseline TxB value was 155.2±42.7ng/mg creatinine. The 3 months-variation of urinary excretion of TxB was -6.5% with warfarin (p=0.197), -29% with apixaban (p<0.001) and -31% with rivaroxaban (p<0.001). Use of anti Xa NOACs was independently associated to the variation of urinary TxB (B: -0.469, p<0.001), after adjustment for clinical characteristics; sGPVI was significantly lower in patients treated with NOACs at 3 months (p<0.001), while only a trend for the warfarin group (p=0.116) was observed. The variation of sGPVI was correlated with that of TxB in the NOACs group (Rs: 0.527, p<0.001). In 15 patients (5 per each group) platelet recruitment was significantly lowered at 3 months by NOACs (p<0.001), but not by warfarin. The study provides evidence that anti Xa NOACs significantly inhibit urinary TxB excretion compared to warfarin, suggesting that NOACs possess antiplatelet property.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2016.09.035DOI Listing
November 2016

Impaired platelet activation in patients with hereditary deficiency of p47.

Br J Haematol 2018 02 10;180(3):454-456. Epub 2016 Oct 10.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14347DOI Listing
February 2018

Low-grade endotoxemia and platelet activation in cirrhosis.

Hepatology 2017 02 5;65(2):571-581. Epub 2016 Nov 5.

Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Patients with cirrhosis may display impaired or enhanced platelet activation, but the reasons for these equivocal findings are unclear. We investigated if bacterial lipopolysaccharide (LPS) is implicated in platelet activation. In a cross-sectional study, conducted in an ambulatory care clinic and hospital, comparing 69 cirrhosis patients and 30 controls matched for sex, age, and atherosclerotic risk factors, serum levels of LPS, soluble cluster of differentiation 40 ligand and p-selectin (two markers of platelet activation), and zonulin (a marker of gut permeability) were investigated. Ex vivo and in vitro studies were also performed to explore the effect of LPS on platelet activation. Compared to controls, cirrhosis patients displayed higher serum levels of LPS (6.0 [4.0-17.5] versus 57.4 [43.4-87.2] pg/mL, P < 0.0001), soluble cluster of differentiation 40 ligand (7.0 ± 2.2 versus 24.4 ± 13.3 ng/mL, P < 0.0001), soluble p-selectin (14.2 ± 4.05 versus 33.2 ± 15.2 ng/mL, P < 0.0001), and zonulin (1.87 ± 0.84 versus 2.54 ± 0.94 ng/mL, P < 0.006). LPS significantly correlated with zonulin (r = 0.45, P < 0.001). Ex vivo studies showed that platelets from cirrhosis patients were more responsive to the agonists independently from platelet count; this phenomenon was blunted by incubation with an inhibitor of Toll-like receptor 4. In vitro study by normal platelets showed that LPS alone (50-150 pg/mL) did not stimulate platelets but amplified platelet response to the agonists; Toll-like receptor 4 inhibitor blunted this effect.

Conclusion: LPS may be responsible for platelet activation and potentially contributes to thrombotic complications occurring in cirrhosis. (Hepatology 2017;65:571-581).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.28853DOI Listing
February 2017
-->