ABSTRACT
AIM: To assess the respective performances of a HCV screening program in a hospital setting and a HCV screening model applied concomitantly in a primary care centre. METHODS: Adult patients consecutively admitted to hospital for ambulatory surgery were screened for anti-HCV antibodies (hospital screening cohort, HPSC), as were patients receiving blood tests for medical reasons in a primary care centre (primary care screening cohort, PCSC). Serum anti-HCV and HCV RNA levels were tested by ELISA and real-time PCR, respectively. RESULTS: Seroprevalence of HCV infection was 2.2 % in the HPSC and 1.4 % in the PCSC (p = 0.044). All viraemic patients (0.2 % in HPSC and 0.1 % in PCSC) were treated with direct-acting antivirals and 85.7 % experienced a sustained virological response. CONCLUSIONS: Hospital-based HCV screening outperformed primary care-centered screening, significantly increasing HCV case findings.
Subject(s)
Hepatitis C, Chronic , Hepatitis C , Adult , Humans , Hepacivirus/genetics , Antiviral Agents/therapeutic use , Seroepidemiologic Studies , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/drug therapy , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hospitals , Hepatitis C Antibodies/therapeutic use , Primary Health CareABSTRACT
The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023-Jan 2024), where a universal immunisation programme began late September (coverage range: 79-99%). High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions. No protection against RSV-negative LRTI-hospitalisations was shown. These interim results could guide public-health decision-making.
Subject(s)
Antibodies, Monoclonal, Humanized , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Respiratory Tract Infections , Infant , Humans , Spain/epidemiology , Antiviral Agents/therapeutic use , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/epidemiology , Hospitalization , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/prevention & control , Respiratory Tract Infections/epidemiology , HospitalsABSTRACT
Background: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself. Methods: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated. Results: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02â ml) than in those without OS (0.04 ± 0.02â ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients. Conclusions: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke.
ABSTRACT
BACKGROUND & AIMS: Advanced hepatic fibrosis is the main risk factor of liver-related morbidity and mortality in patients with chronic liver disease. In this study, we assessed the potential role of bone morphogenetic protein 8A (BMP8A) as a novel target involved in liver fibrosis progression. METHODS: Histological assessment and BMP8A expression were determined in different murine models of hepatic fibrosis. Furthermore, serum BMP8A was measured in mice with bile duct ligation (BDL), in 36 subjects with histologically normal liver (NL) and in 85 patients with biopsy-proven non-alcoholic steatohepatitis (NASH): 52 with non- or mild fibrosis (F0-F2) and 33 with advanced fibrosis (F3-F4). BMP8A expression and secretion was also determined in cultured human hepatocyte-derived (Huh7) and human hepatic stellate (LX2) cells stimulated with transforming growth factor êµ (TGFêµ). RESULTS: Bmp8a mRNA levels were significantly upregulated in livers from fibrotic mice compared to control animals. Notably, serum BMP8A levels were also elevated in BDL mice. In addition, in vitro experiments showed increased expression and secretion to the culture supernatant of BMP8A in both Huh7 and LX2 cells treated with TGFêµ. Noteworthy, we found that serum BMP8A levels were significantly higher in NASH patients with advanced fibrosis than in those with non- or mild fibrosis. In fact, the AUROC of circulating BMP8A concentrations to identify patients with advanced fibrosis (F3-F4) was 0.74 (pË0.0001). Moreover, we developed an algorithm based on serum BMP8A levels that showed an AUROC of 0.818 (pË0.0001) to predict advanced fibrosis in NASH patients. CONCLUSION: This study provides experimental and clinical evidence indicating that BMP8A is a novel molecular target linked to liver fibrosis and introduces an efficient algorithm based on serum BMP8A levels to screen patients at risk for advanced hepatic fibrosis.
Subject(s)
Hepatitis, Alcoholic , Non-alcoholic Fatty Liver Disease , Humans , Electron Transport , Patient AcuityABSTRACT
BACKGROUND AND AIMS: Little is known about the extent of mitochondrial respiratory chain (MRC) activity dysfunction in patients with alcoholic hepatitis (AH). We aimed to assess the hepatic MRC activity in AH patients and its potential impact on the severity and prognosis of this life-threatening liver disease. METHODS: MRC complexes were measured in liver biopsies of 98 AH patients (non-severe, 17; severe, 81) and in 12 histologically normal livers (NL). Severity was assessed according to Maddrey's Index and MELD score. Corticosteroid response rate and cumulative mortality were also evaluated. RESULTS: The activity of the five MRC complexes was markedly decreased in the liver of AH patients compared with that of NL subjects, being significantly lower in patients with severe AH than in those with non-severe AH. There was a negative correlation between the activity of all MRC complexes and the severity of AH. Interestingly, only complex I and III activities showed a significant positive correlation with the corticosteroid response rate and a significant negative correlation with the mortality rate at all-time points studied. In a multivariate regression analysis, besides the MELD score and the corticosteroid response rate, complex I activity was significantly associated with 3-month mortality (OR = 6.03; p = 0.034) and complex III activity with 6-month mortality (OR = 4.70; p = 0.041) in AH patients. CONCLUSION: Our results indicate that MRC activity is markedly decreased in the liver of AH patients, and, particularly, the impairment of MRC complexes I and III activity appears to have a significant impact on the clinical outcomes of patients with AH.
Subject(s)
Hepatitis, Alcoholic , Humans , Electron Transport , Prognosis , Adrenal Cortex Hormones , Severity of Illness IndexABSTRACT
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being non-alcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about its involvement in NAFLD onset and progression. This study aimed to elucidate the impact of BMP2 in NAFLD pathophysiology. METHODS: Hepatic and circulating levels of BMP2 were quantified in serum and liver specimens from 115 biopsy-proven NAFLD patients and 75 subjects with histologically normal liver (NL). In addition, BMP2 content and release was determined in cultured human hepatocytes upon palmitic acid (PA) overload. RESULTS: We found that BMP2 expression was abnormally increased in livers from NAFLD patients than in subjects with NL and this was reflected in higher serum BMP2 levels. Notably, we observed that PA upregulated BMP2 expression and secretion by human hepatocytes. An algorithm based on serum BMP2 levels and clinically relevant variables to NAFLD showed an AUROC of 0.886 (95%CI, 0.83-0.94) to discriminate NASH. We used this algorithm to develop SAN (Screening Algorithm for NASH): a SAN < 0.2 implied a low risk and a SAN ≥ 0.6 indicated high risk of NASH diagnosis. CONCLUSION: This proof-of-concept study shows BMP2 as a new molecular target linked to NAFLD and introduces SAN as a simple and efficient algorithm to screen individuals at risk for NASH.
ABSTRACT
Introduction: Given that obstructive sleep apnea (OSA) is commonly associated with metabolic disorders, in this prospective study, we sought to determine the prevalence and risk factors for hepatosteatosis, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis in patients with clinical and polygraphic criteria of OSA (n = 153) and in subjects with normal lung function parameters (NLP, n = 43). Methods: Hepatosteatosis, NASH, and advanced liver fibrosis were determined by blood-based non-invasive tools, such as the fatty liver index and the hepatic steatosis index, a serum lipidomic (OWLiver™) test, and three distinct fibrosis algorithms, respectively. Logistic regression models adjusted by potential confounders were performed to evaluate risk factors. Results: Insulin resistance and dyslipidemia were more frequent in patients with OSA than in subjects with NLP. The prevalence of hepatosteatosis was significantly higher in patients with OSA than in subjects with NLP. NASH was also found more frequently in patients with OSA than in subjects with NLP. In contrast, advanced liver fibrosis was rarely detected in the entire study population, and no significant differences were observed between patients with OSA and subjects with NLP. Besides male gender, increased body mass index (BMI), and presence of type 2 diabetes, percentage of sleep time with oxygen saturation <90% (Tc90%) was the only polygraphic variable significantly associated with NASH in patients with OSA. Conclusions: This study shows that hepatosteatosis and NASH are highly prevalent in patients with OSA and indicates that those with a Tc90% higher than 10% are at increased risk for NASH.
ABSTRACT
Fitbit es conocida básicamente por su capacidad de seguimiento de actividades, y la App es una herramienta adicional para ello. La App puede contar los pasos, las calorías quemadas, y junto con otros productos Fitbit puede incluso grabar otras informaciones útiles como la presión sanguínea, los niveles de glucosa o los patrones de sueño. El objetivo del artículo de opinión es realizar una revisión de Fitbit, una app de la categoría de deportes y salud, que puede tener aplicaciones clínicas importantes(AU)
Fitbit is basically known for its ability to track activities, and the App is an additional tool for this. The App can count the steps, the calories burned, and along with other products Fitbit can even record other useful information such as blood pressure, glucose levels or sleep patterns. The objective of the opinion article is to carry out a review of Fitbit, an app in the sports and health category, which may have important clinical applications(AU)
Subject(s)
Humans , Mobile Applications , Fitness Trackers/standards , Motor Activity/ethics , Sports/educationABSTRACT
Abdominal aortic aneurysm (AAA) evolution is unpredictable and no specific treatment exists for AAA, except surgery to prevent aortic rupture. Galectin-3 has been previously associated with CVD, but its potential role in AAA has not been addressed. Galectin-3 levels were increased in the plasma of AAA patients (n=225) compared with the control group (n=100). In addition, galectin-3 concentrations were associated with the need for surgical repair, independently of potential confounding factors. Galectin-3 mRNA and protein expression were increased in human AAA samples compared with healthy aortas. Experimental AAA in mice was induced via aortic elastase perfusion. Mice were treated intravenously with the galectin-3 inhibitor modified citrus pectin (MCP, 10 mg/kg, every other day) or saline. Similar to humans, galectin-3 serum and aortic mRNA levels were also increased in elastase-induced AAA mice compared with control mice. Mice treated with MCP showed decreased aortic dilation, as well as elastin degradation, vascular smooth muscle cell (VSMC) loss, and macrophage content at day 14 postelastase perfusion compared with control mice. The underlying mechanism(s) of the protective effect of MCP was associated with a decrease in galectin-3 and cytokine (mainly CCL5) mRNA and protein expression. Interestingly, galectin-3 induced CCL5 expression by a mechanism involving STAT3 activation in VSMC. Accordingly, MCP treatment decreased STAT3 phosphorylation in elastase-induced AAA. In conclusion, increased galectin-3 levels are associated with AAA progression, while galectin-3 inhibition decreased experimental AAA development. Our data suggest the potential role of galectin-3 as a therapeutic target in AAA.
Subject(s)
Aorta, Abdominal/drug effects , Aortic Aneurysm, Abdominal/prevention & control , Galectin 3/antagonists & inhibitors , Galectin 3/blood , Pancreatic Elastase , Pectins/pharmacology , Animals , Aorta, Abdominal/enzymology , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/blood , Aortic Aneurysm, Abdominal/enzymology , Aortic Aneurysm, Abdominal/pathology , Blood Proteins , Case-Control Studies , Cells, Cultured , Chemokine CCL5/genetics , Chemokine CCL5/metabolism , Dilatation, Pathologic , Disease Models, Animal , Disease Progression , Galectin 3/genetics , Galectin 3/metabolism , Galectins , Humans , Mice, Inbred C57BL , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Phosphorylation , RNA, Messenger/blood , RNA, Messenger/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Time Factors , Up-RegulationABSTRACT
Introducción: El marketing social es una disciplina de la mercadotecnia dirigida a influir en el comportamiento de las personas a fin de que mejoren su bienestar y el de la sociedad. Por sus características tiene potencialidades de influir en la solución de problemas de salud a nivel individual, grupal y social, en especial desde el punto de vista de las acciones de comunicación a aplicarse, como las actividades sociales, campañas sociales, charlas, relaciones públicas, ruedas de prensa, entre otras. Objetivo: El objetivo del artículo es valorar a partir del criterio de expertos, la influencia que puede ejercer el marketing social en la solución de problemas de salud en Ecuador. Métodos: Se aplicó un cuestionario para conocer el criterio de 10 especialistas de las ciencias médicas y administrativas de Ecuador, en función de la influencia que pueden ejercer los instrumentos y estrategias de comunicación de marketing social en la solución de problemas de salud. El procesamiento de los datos se realizó con Microsoft Excel, para determinar el comportamiento descriptivo de los mismos y de forma inferencial a través del Coeficiente R de Pearson. Resultados: A partir del criterio de los expertos se determinó la importancia de las actividades sociales para la solución de problemas de salud en Ecuador, en especial las campañas sociales explicativas y de desmotivación de vicios, así como los mensajes de motivación. Destacan como principales objetos de las campañas las enfermedades epidémicas y del desarrollo, y el gobierno nacional como principal agente de marketing social. Mientras que la comunidad tiene una baja participación y negativas relaciones con otras variables estudiadas. El control del proceso de comunicación limita la efectividad de las acciones de marketing social. Conclusiones: El análisis empírico desarrollado a partir del criterio de expertos permitió diagnosticar la influencia que ejerce el marketing social en la solución de problemas de salud, así como los principales instrumentos de comunicación que se emplean, los agentes más activos y algunas insuficiencias en el proceso(AU)
Introduction: Social marketing is a discipline of marketing aimed at influencing people's behavior in order to improve their well-being and that of society. Because of its characteristics, it has the potential to influence the solution of health problems at the individual, group and social level, especially from the point of view of communication actions to be applied, such as social activities, social campaigns, talks, public relations, press conferences, among others. Objective: The objective of the article is to evaluate, based on the criterion of experts, the influence that social marketing can exert on solving health problems in Ecuador. Methods: A questionnaire was applied to know the criteria of 10 specialists from the medical and administrative sciences of Ecuador, depending on the influence that can be exerted on the instruments and strategies of communication of social marketing in the solution of health problems. The data processing was done with Microsoft Excel, to determine the descriptive behavior of the same and inferential form through Pearson R Coefficient. Results: Based on the criteria of the experts, the importance of social activities for the solution of health problems in Ecuador was determined, especially the explanatory social campaigns and demotivation of vices, as well as motivational messages. The epidemic and developmental diseases are highlighted as the main objects of the campaigns, and the national government is the main agent of social marketing. While the community has low participation and negative relationships with other variables studied. Controlling the communication process limits the effectiveness of social marketing actions. Conclusions: The empirical analysis developed from the expert criterion allowed to diagnose the influence of social marketing in the solution of health problems, as well as the main communication tools used, the most active agents and some shortcomings in the process(AU)
Subject(s)
Humans , Marketing of Health Services/methods , Social Marketing/ethics , Epidemiology, Descriptive , Health Communication , Health Promotion/methodsABSTRACT
AIMS: To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Expression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real-time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2-/-). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2-/- mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2-/- or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2-/- mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG. CONCLUSION: Either Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA.
Subject(s)
Antibodies/pharmacology , Aorta, Abdominal/drug effects , Aortic Aneurysm, Abdominal/prevention & control , Lipocalin-2/antagonists & inhibitors , Lipocalin-2/deficiency , Animals , Aorta, Abdominal/metabolism , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/metabolism , Aortic Aneurysm, Abdominal/pathology , Case-Control Studies , Cells, Cultured , Chemotaxis, Leukocyte/drug effects , Dilatation, Pathologic , Disease Models, Animal , Elastin/metabolism , Genetic Predisposition to Disease , Humans , Lipocalin-2/genetics , Lipocalin-2/immunology , Lipocalin-2/metabolism , Matrix Metalloproteinases/metabolism , Mice, Inbred C57BL , Mice, Knockout , Microvessels/drug effects , Microvessels/metabolism , Microvessels/pathology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Neutrophil Infiltration/drug effects , Phenotype , RNA, Messenger/genetics , RNA, Messenger/metabolism , Time FactorsABSTRACT
Abdominal aortic aneurysm (AAA) is a permanent dilation of the aorta due to excessive proteolytic, oxidative and inflammatory injury of the aortic wall. We aimed to identify novel mediators involved in AAA pathophysiology, which could lead to novel therapeutic approaches. For that purpose, plasma from four AAA patients and four controls were analysed by a label-free proteomic approach. Among identified proteins, paraoxonase-1 (PON1) was decreased in plasma of AAA patients compared with controls, which was further validated in a bigger cohort of samples by ELISA. The phenylesterase enzymatic activity of PON1 was also decreased in serum of AAA patients compared with controls. To address the potential role of PON1 as a mediator of AAA, experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and human transgenic PON1 (HuTgPON1) mice. Similar to humans, PON1 activity was also decreased in serum of elastase-induced AAA mice compared with healthy mice. Interestingly, overexpression of PON1 was accompanied by smaller aortic dilation and higher elastin and vascular smooth muscle cell (VSMC) content in the AAA of HuTgPON1 compared with WT mice. Moreover, HuTgPON1 mice display decreased oxidative stress and apoptosis, as well as macrophage infiltration and monocyte chemoattractant protein-1 (MCP1) expression, in elastase-induced AAA. In conclusion, decreased circulating PON1 activity is associated with human and experimental AAA. PON1 overexpression in mice protects against AAA progression by reducing oxidative stress, apoptosis and inflammation, suggesting that strategies aimed at increasing PON1 activity could prevent AAA.
Subject(s)
Aortic Aneurysm, Abdominal/metabolism , Aryldialkylphosphatase/metabolism , Animals , Aortic Aneurysm, Abdominal/prevention & control , Apoptosis/drug effects , Disease Models, Animal , Disease Progression , Humans , Inflammation/metabolism , Macrophages/metabolism , Male , Mice , Mice, Transgenic , Proteomics/methodsABSTRACT
To assess the potential association between TRX-1/PRX-1 and NADPH oxidase (Nox) activity in vivo and in vitro, TRX-1/PRX-1 levels were assessed by ELISA in 84 asymptomatic subjects with known phagocytic NADPH oxidase activity and carotid intima-media thickness (IMT). We found a positive correlation between TRX-1/PRX-1 and NADPH oxidase-dependent superoxide production (r=0.48 and 0.47; p<0.001 for both) and IMT (r=0.31 and 0.36; p<0.01 for both) adjusted by age and sex. Moreover, asymptomatic subjects with plaques have higher PRX-1 and TRX plasma levels (p<0.01 for both). These data were confirmed in a second study in which patients with carotid atherosclerosis showed higher PRX-1 and TRX plasma levels than healthy subjects (p<0.001 for both). In human atherosclerotic plaques, the NADPH oxidase subunit p22phox colocalized with TRX-1/PRX-1 in macrophages (immunohistochemistry). In monocytes and macrophages, phorbol 12-myristate 13-acetate (PMA) induced NADPH activation and TRX-1/PRX-1 release to the extracellular medium, with a concomitant decrease in their intracellular levels, which was reversed by the NADPH inhibitor apocynin (Western blot). In loss-of-function experiments, genetic silencing of the NADPH oxidase subunit Nox2 blocked PMA-induced intracellular TRX-1/PRX-1 downregulation in macrophages. Furthermore, the PMA-induced release of TRX-1/PRX-1 involves the modulation of their redox status and exosome-like vesicles. TRX-1/PRX-1 levels are associated with NADPH oxidase-activity in vivo and in vitro. These data could suggest a coordinated antioxidant response to oxidative stress in atherothrombosis.
Subject(s)
Carotid Artery Diseases/enzymology , NADPH Oxidases/metabolism , Peroxiredoxins/blood , Thioredoxins/blood , Aged , Asymptomatic Diseases , Biomarkers/blood , Carotid Artery Diseases/blood , Carotid Artery Diseases/diagnostic imaging , Carotid Intima-Media Thickness , Case-Control Studies , Cell Line , Female , Humans , Macrophages/enzymology , Male , Middle Aged , Oxidative Stress , Protein TransportABSTRACT
BACKGROUND: Galectin-3 (Gal-3) participates in different mechanisms involved in atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Thus, there have been committed intensive efforts to elucidate the function of Gal-3 in cardiovascular (CV) diseases. The role of Gal-3 as a circulating biomarker has been demonstrated in patients with heart failure, but its importance as a biomarker in atherothrombosis is still unknown. METHODS AND RESULTS: Because Gal-3 is involved in monocyte-to-macrophage transition, we used fresh isolated monocytes and the in vitro model of macrophage differentiation of THP-1 cells stimulated with phorbol myristate acetate (PMA). Gal-3 release is increased by PMA in human monocytes and macrophages, a process involving exosomes and regulated by reactive oxygen species/NADPH oxidase activity. In asymptomatic subjects (n=199), Gal-3 plasma levels are correlated with NADPH oxidase activity in peripheral blood mononuclear cells (r=0.476; P<0.001) and carotid intima-media thickness (r=0.438; P<0.001), a surrogate marker of atherosclerosis. Accordingly, Gal-3 plasma concentrations are increased in patients with carotid atherosclerosis (n=158), compared to control subjects (n=115; 14.3 [10.7 to 16.9] vs. 10.4 [8.6 to 12.5] ng/mL; P<0.001). Finally, on a 5-year follow-up study in patients with peripheral artery disease, Gal-3 concentrations are significantly and independently associated with an increased risk for CV mortality (hazard ratio=2.24, 95% confidence interval: 1.06 to 4.73, P<0.05). CONCLUSIONS: Gal-3 extracellular levels could reflect key underlying mechanisms involved in atherosclerosis etiology, development, and plaque rupture, such as inflammation, infiltration of circulating cells and oxidative stress. Moreover, circulating Gal-3 concentrations are associated with clinical outcomes in patients with atherothrombosis.
Subject(s)
Carotid Artery Diseases/blood , Galectin 3/blood , Oxidative Stress , Peripheral Arterial Disease/blood , Aged , Biomarkers , Carotid Artery Diseases/diagnostic imaging , Carotid Intima-Media Thickness , Case-Control Studies , Cell Line , Female , Follow-Up Studies , Galectin 3/drug effects , Humans , In Vitro Techniques , Inflammation , Macrophages , Male , Middle Aged , Monocytes , NADPH Oxidases/metabolism , Peripheral Arterial Disease/mortality , Prognosis , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
Oxidative stress is involved in the chronic pathological vascular remodelling of both abdominal aortic aneurysm and occlusive atherosclerosis. Red blood cells (RBCs), leukocytes and platelets present in both, aneurysmal intraluminal thrombus and intraplaque haemorraghes, could be involved in the redox imbalance inside diseased arterial tissues. RBCs haemolysis may release the pro-oxidant haemoglobin (Hb), which transfers heme to tissue and low-density lipoproteins. Heme-iron potentiates molecular, cell and tissue toxicity mediated by leukocytes and other sources of reactive oxygen species (ROS). Polymorphonuclear neutrophils release myeloperoxidase and, along with activated platelets, produce superoxide mediated by NADPH oxidase, causing oxidative damage. In response to this pro-oxidant milieu, several antioxidant molecules of plasma or cell origin can prevent ROS production. Free Hb binds to haptoglobin (Hp) and once Hp-Hb complex is endocytosed by CD163, liberated heme is converted into less toxic compounds by heme oxygenase-1. Iron homeostasis is mainly regulated by transferrin, which transports ferric ions to other cells. Transferrin-bound iron is internalised via endocytosis mediated by transferrin receptor. Once inside the cell, iron is mainly stored by ferritin. Other non hemo-iron related antioxidant enzymes (e.g. superoxide dismutase, catalase, thioredoxin and peroxiredoxin) are also involved in redox modulation in vascular remodelling. Oxidative stress is a main determinant of chronic pathological remodelling of the arterial wall, partially linked to the presence of RBCs, leukocytes, platelets and oxidised fibrin within tissue and to the imbalance between pro-/anti-oxidant molecules. Understanding the complex mechanisms underlying redox imbalance could help to define novel potential targets to decrease atherothrombotic risk.
Subject(s)
Blood Platelets/metabolism , Erythrocytes/metabolism , Leukocytes/metabolism , Oxidative Stress , Animals , Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , Antioxidants/therapeutic use , Aortic Aneurysm, Abdominal/blood , Aortic Aneurysm, Abdominal/drug therapy , Atherosclerosis/blood , Atherosclerosis/drug therapy , Catalase/blood , Chelation Therapy , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Haptoglobins/metabolism , Heme/metabolism , Heme Oxygenase-1/blood , Humans , Iron/blood , Peroxidase/blood , Peroxiredoxins/blood , Platelet Activation , Reactive Oxygen Species/metabolism , Receptors, Cell Surface/blood , Respiratory Burst , Superoxide Dismutase/blood , Thioredoxins/bloodABSTRACT
Cell stress proteins (CSPS) are a large and heterogeneous family of proteins, sharing two main characteristics: their levels and/or location are modified under stress and most of them can exert a chaperon function inside the cells. Nonetheless, they are also involved in the modulation of several mechanisms, both at the intracellular and the extracellular compartments. There are more than 100 proteins belonging to the CSPs family, among them the thioredoxin (TRX) system, which is the focus of the present paper. TRX system is composed of several proteins such as TRX and peroxiredoxin (PRDX), two thiol-containing enzymes that are key players in redox homeostasis due to their ability to scavenge potential harmful reactive oxygen species. In addition to their main role as antioxidants, recent data highlights their function in several processes such as cell signalling, immune inflammatory responses, or apoptosis, all of them key mechanisms involved in atherothrombosis. Moreover, since TRX and PRDX are present in the pathological vascular wall and can be secreted under prooxidative conditions to the circulation, several studies have addressed their role as diagnostic, prognostic, and therapeutic biomarkers of cardiovascular diseases (CVDs).
Subject(s)
Atherosclerosis/complications , Atherosclerosis/metabolism , Heat-Shock Proteins/metabolism , Thrombosis/complications , Thrombosis/metabolism , Animals , Humans , Models, Biological , Peroxiredoxins/metabolism , Thioredoxins/metabolismABSTRACT
AIMS: Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells. CONCLUSION: Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.