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1.
Front Immunol ; 10: 1621, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379826

RESUMO

Background: Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1ß and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations. Methods and Results: WT, Nlrp3 -/-, and ASC -/- (Pycard -/-) male mice were exposed to high fat diet (HFD; 60 cal% fat) or control diet for 52 weeks. Cardiac structure and function were evaluated by echocardiography and magnetic resonance imaging, respectively. Whereas, NLRP3 and ASC deficiency did not affect the cardiac hypertrophic response to obesity, it was preventive against left ventricle concentric remodeling and impairment of diastolic function. Furthermore, whereas NLRP3 and ASC deficiency attenuated systemic inflammation in HFD fed mice; long-term HFD did not induce significant cardiac fibrosis or inflammation, suggesting that the beneficial effects of NLRP3 inflammasome deficiency on myocardial remodeling at least partly reflect systemic mechanisms. Nlrp3 and ASC (Pycard) deficient mice were also protected against obesity-induced systemic metabolic dysregulation, as well as lipid accumulation and impaired insulin signaling in hepatic and cardiac tissues. Conclusions: Our data indicate that the NLRP3 inflammasome modulates cardiac concentric remodeling in obesity through effects on systemic inflammation and metabolic disturbances, with effect on insulin signaling as a potential mediator within the myocardium.

2.
J Am Coll Cardiol ; 74(6): 774-782, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31395128

RESUMO

BACKGROUND: The chemokines CCL19 and CCL21 are up-regulated in atherosclerotic disease and heart failure, and increased circulating levels are found in unstable versus stable coronary artery disease. OBJECTIVES: The purpose of this study was to evaluate the prognostic value of CCL19 and CCL21 in acute coronary syndrome (ACS). METHODS: CCL19 and CCL21 levels were analyzed in serum obtained from ACS patients (n = 1,146) on the first morning after hospital admission. Adjustments were made for GRACE (Global Registry of Acute Coronary Events) score, left ventricular ejection fraction, pro-B-type natriuretic peptide, troponin I, and C-reactive protein levels. RESULTS: The major findings were: 1) those having fourth quartile levels of CCL21 on admission of ACS had a significantly higher long-term (median 98 months) risk of major adverse cardiovascular events (MACE) and myocardial infarction in fully adjusted multivariable models; 2) high CCL21 levels at admission were also independently associated with MACE and cardiovascular mortality during short-time (3 months) follow-up; and 3) high CCL19 levels at admission were associated with the development of heart failure. CONCLUSIONS: CCL21 levels are independently associated with outcome after ACS and should be further investigated as a promising biomarker in these patients.

4.
J Immunol ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427442

RESUMO

NAD+ is an essential cofactor in reduction-oxidation metabolism with impact on metabolic and inflammatory diseases. However, data elucidating the effects of NAD+ on the proinflammatory features of human primary monocytes are scarce. In this study, we explored how NAD+ affects TLR4 and NOD-like receptor with a PYD-domain 3 (NLRP3) inflammasome activation, two key innate immune responses. Human primary monocytes were isolated from buffy coats obtained from healthy individuals. Intracellular NAD+ was manipulated by nicotinamide riboside and the NAMPT inhibitor FK866. Cells were primed with LPS with or without subsequent NLRP3 activation with ATP or cholesterol crystals to analyze the effects of NAD+ levels on TLR4-mediated NF-κB activation and NLRP3 activity, respectively. Cytokine release was quantified, and the downstream signal pathway of TLR4 was investigated with Western blot and proteomic analysis. The impact of sirtuin and PARP inhibition was also explored. Our main findings were: 1) elevated NAD+ enhanced IL-1ß release in LPS-primed human monocytes exposed to ATP in vitro, 2) both NLRP3-dependent and -independent inflammatory responses in LPS-exposed monocytes were inhibited by NAD+ depletion with FK866, 3) the inhibition was not caused by suppression of sirtuins or PARP1, and 4) phosphorylation of several proteins TLR4 signal pathway was inhibited by FK866-mediated NAD+ depletion, specifically TAK1, IKKß, IkBα, MEK 1/2, ERK 1/2, and p38. Hence, we suggest a novel mechanism in which NAD+ affects TLR4 signal transduction. Furthermore, our data challenge previous reports of the interaction between NAD+ and inflammation and question the use of nicotinamide riboside in the therapy of inflammatory disorders.

5.
Int J Cancer ; 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31444972

RESUMO

Angiogenesis is necessary for tumor growth and has been targeted in breast cancer, however, it is unclear which patients will respond and benefit from anti-angiogenic therapy. We report non-invasive monitoring of patient response to neoadjuvant chemotherapy given alone or in combination with anti-VEGF (bevacizumab) in a randomized clinical trial. At four time points during neoadjuvant chemotherapy ± bevacizumab of Her2-negative breast cancers, we measured metabolites and inflammation-related markers in patient's serum. We report significant changes in the levels of several molecules induced by bevacizumab, the most prominent being an increase in pentraxin 3 (PTX3) and von Willebrand factor (VWF). Serum levels of AXL, VWF and pulmonary and activation-regulated cytokine (PARC/CCL18) reflected response to chemotherapy alone or in combination with bevacizumab. We further analyzed serum cytokines in relation to tumor characteristics such as gene expression, tumor metabolites and tumor infiltrating leukocytes. We found that VWF and growth-differentiation factor 15 (GDF15) tumor mRNA levels correlated with their respective serum protein levels suggesting that these cytokines may be produced by tumors and outflow to the bloodstream while influencing the tumor microenvironment locally. Finally, we used binomial logistic regression which allowed to predict patient's response using only 10 non-invasive biomarkers. Our study highlights the potential of monitoring circulating levels of cytokines and metabolites during breast cancer therapy. This article is protected by copyright. All rights reserved.

6.
Sci Rep ; 9(1): 9427, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263122

RESUMO

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency, characterized by inadequate antibody responses and recurrent bacterial infections. Paradoxically, a majority of CVID patients have non-infectious inflammatory and autoimmune complications, associated with systemic immune activation. Our aim was to explore if HDL, known to have anti-inflammatory properties, had impaired function in CVID patients and thereby contributed to their inflammatory phenotype. We found reduced HDL cholesterol levels in plasma of CVID patients compared to healthy controls, particularly in patients with inflammatory and autoimmune complications, correlating negatively with inflammatory markers CRP and sCD25. Reverse cholesterol transport capacity testing showed reduced serum acceptance capacity for cholesterol in CVID patients with inflammatory and autoimmune complications. They also had reduced cholesterol efflux capacity from macrophages to serum and decreased expression of ATP-binding cassette transporter ABCA1. Human HDL suppressed TLR2-induced TNF release less in blood mononuclear cells from CVID patients, associated with decreased expression of transcriptional factor ATF3. Our data suggest a link between impaired HDL function and systemic inflammation in CVID patients, particularly in those with autoimmune and inflammatory complications. This identifies HDL as a novel therapeutic target in CVID as well as other more common conditions characterized by sterile inflammation or autoimmunity.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31301965

RESUMO

BACKGROUND: Alterations in the partly microbiota-dependent carnitine-γ-butyrobetaine (γBB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection. METHODS: We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound. RESULTS: Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant. CONCLUSIONS: Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.

8.
Br J Nutr ; : 1-24, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31262370

RESUMO

Elevated lipoprotein (a) (Lp[a]) is associated with cardiovascular disease (CVD) and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FAs) in the regulation of Lp(a), however, no studies have investigated the association between plasma Lp(a) concentration and omega-6 FAs. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary omega-6 FA intake, and plasma levels of arachidonic acid in subjects with familial hypercholesterolemia (FH). We included FH subjects with (n=68) and without (n=77) elevated Lp(a) defined as ≥75 nmol/L, and healthy subjects (n=14). Total fatty acid profile was analyzed by Gas Chromatography-Flame Ionization Detector analysis, and the daily intake of macronutrients (including the sum of omega-6 FAs: 18:2n-6, 20:2n-6, 20:3n-6 and 20:4n-6) were computed from completed food frequency questionnaires. FH subjects with elevated Lp(a) had higher plasma levels of arachidonic acid (AA) compared to FH subjects without elevated Lp(a) (P=0.03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared to controls (P<0.001). The multivariable analyses showed associations between dietary omega-6 FA intake and plasma levels of AA (P=0.02), and between plasma levels of Lp(a) and AA (P=0.006). Our data suggest a novel link between plasma Lp(a) concentration, dietary omega-6 FAs and plasma AA concentration, which may contribute to explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a).

9.
Artigo em Inglês | MEDLINE | ID: mdl-31356551

RESUMO

Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems are evolutionarily conserved throughout species. As a result, the immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interaction between metabolic disturbances and the immune system has been most extensively studied in disorders related to obesity such as insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease. Metabolically induced inflammation seems also to play a role in the development and progression of atherosclerosis including its complications such as myocardial infarction (MI) and post-MI remodelling. There are several lines of evidence suggesting that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a sensor of metabolic stress linking metabolic disturbances to inflammation. Here we will discuss the role of the NLRP3 inflammasome in the pathogenesis of obesity and diabetes, two important risk factors for atherosclerosis and MI. We will also discuss the role of NLRP3 inflammasome in the interaction between metabolic disturbances and myocardial inflammation during MI and during metabolically induced myocardial remodelling.

10.
EBioMedicine ; 46: 264-273, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31345784

RESUMO

BACKGROUND: Termination of acute inflammation is an active process orchestrated by lipid mediators (LM) derived from polyunsaturated fatty acids, referred to as specialized pro-resolving mediators (SPM). These mediators also provide novel therapeutic opportunities for treating inflammatory disease. However, the regulation of these molecules following acute myocardial infarction (MI) remains of interest. METHODS: In this prospective observational study we aimed to profile plasma levels of SPMs in ST-elevation MI (STEMI) patients during the first week following MI. Plasma LM concentrations were measured in patients with STEMI (n = 15) at three time points and compared with stable coronary artery disease (CAD; n = 10) and healthy controls (n = 10). FINDINGS: Our main findings were: (i) Immediately after onset of MI and before peak troponin T levels, STEMI patients had markedly increased levels of SPMs as compared with healthy controls and stable CAD patients, with levels of these mediators declining during follow-up. (ii) The increase in SPMs primarily reflected an increase in docosapentaenoic acid- and docosahexaenoic acid-derived protectins. (iii) Several individual protectins were correlated with the rapid increase in neutrophil counts, but not with CRP. (iv) A shift in 5-LOX activity from the leukotriene B4 pathway to the pro-resolving RvTs was observed. INTERPRETATION: The temporal regulation of SPMs indicates that resolution mechanisms are activated early during STEMI as part of an endogenous mechanism to initiate repair. Thus strategies to boost the activity and/or efficacy of these endogenous mechanisms may represent novel therapeutic opportunities for treatment of patients with MI. FUND: This work was supported by grants from the South-Eastern Norwegian regional health authority, the European Research Council under the European Union's Horizon 2020 research and innovation program, a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society, and the Barts Charity.

11.
J Thromb Haemost ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31220397

RESUMO

BACKGROUND: Animal and observational studies have suggested a pathophysiological role for complement in venous thromboembolism (VTE), but the initiating mechanisms are unknown. Mannose-binding lectin (MBL) bound to altered host cells leads to activation of the lectin complement pathway, and both high and low MBL levels have been implicated in the pathophysiology of cardiovascular disease. OBJECTIVES: To investigate the association between plasma MBL levels and future risk of incident VTE. METHODS: We conducted a nested case-control study in 417 VTE patients and 849 age-matched and sex-matched controls derived from the general population (Tromsø Study). Plasma MBL levels were measured using enzyme-linked immunosorbent assay. Logistic regression models were used to estimate odds ratio (OR) for VTE across quartiles of plasma MBL levels. RESULTS: Subjects with plasma MBL levels in the lowest quartile (<435 ng/mL) had a reduced OR for overall VTE (OR 0.79, 95% confidence interval [CI]: 0.56-1.10) and for DVT (OR 0.70, 95% CI: 0.47-1.04) compared to those with MBL in the highest quartile (≥2423 ng/mL) after multivariable adjustments. For VTE, DVT, and pulmonary embolism (PE) the ORs decreased substantially with decreasing time between blood sampling and VTE event. CONCLUSIONS: Our findings suggest that low plasma MBL levels are associated with reduced risk of VTE, and DVT in particular.

12.
Front Immunol ; 10: 1285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244838

RESUMO

Background: IL-1ß is a highly potent pro-inflammatory cytokine and its secretion is tightly regulated. Inactive pro-IL-1ß is transcribed in response to innate immune receptors activating NFκB. If tissue damage occurs, danger signals released from necrotic cells, such as ATP, can activate NLRP3-inflammasomes (multiprotein complexes consisting of NLRP3, ASC, and active caspase-1) which cleaves and activates pro-IL-1ß. NLRP3 activation also depends on NEK7 and mitochondrial ROS-production. Thus, IL-1ß secretion may be regulated at the level of each involved component. We have previously shown that NLRP3-dependent IL-1ß release can be induced in cardiac fibroblasts by pro-inflammatory stimuli. However, anti-inflammatory mechanisms targeting IL-1ß release in cardiac cells have not been investigated. mTOR is a key regulator of protein metabolism, including autophagy and proteasome activity. In this study we explored whether autophagy or proteasomal degradation are regulators of NLRP3 inflammasome activation and IL-1ß release from cardiac fibroblasts. Methods and Results: Serum starvation selectively reduced LPS/ATP-induced IL-1ß secretion from cardiac fibroblasts. However, no other inflammasome components, nor mitochondrial mass, were affected. The mTOR inhibitor rapamycin restored pro-IL-1ß protein levels as well as LPS/ATP-induced IL-1ß release from serum starved cells. However, neither serum starvation nor rapamycin induced autophagy in cardiac fibroblasts. Conversely, chloroquine and bafilomycin A (inhibitors of autophagy) and betulinic acid (a proteasome activator) effectively reduced LPS-induced pro-IL-1ß protein levels. Key findings were reinvestigated in human monocyte-derived macrophages. Conclusion: In cardiac fibroblasts, mTOR inhibition selectively favors pro-IL-1ß synthesis while proteasomal degradation and not autophagy is the major catabolic anti-inflammatory mechanism for degradation of this cytokine.

13.
Scand Cardiovasc J ; 53(4): 213-219, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31169417

RESUMO

Objectives. Exercise training has been proposed to have anti-inflammatory effects. We examined whether aerobic interval training (AIT) can attenuate the inflammatory response in ischemic heart failure (HF) as measured by serum biomarkers representing a broad spectrum of activated inflammatory pathways. Design. We conducted a controlled prospective trial recruiting 30 patients (19 in the AIT group and 11 in the control group) with ischemic HF and an implantable cardioverter defibrillator (ICD). This study is a sub study of the previously reported "Aerobic interval training in patients with heart failure and an ICD" (Eur J Prev Cardiol. 22 March 2015; 22:296-303). Patients in the AIT group exercised for 12-weeks completing a total of 36 AIT sessions. We analyzed serum levels of C-reactive protein, pentraxin-3, osteoprotegerin, brain natriuretic peptide, neopterin, and soluble tumor necrois factor type 1 and 2, all known to predict an adverse outcome in HF, at baseline and following the 12-week AIT intervention. Results. The AIT group significantly increased peak oxygen uptake and improved endothelial function compared to the sedentary control group. No statistically significant changes in serum levels of the biomarkers were detected from baseline following the AIT intervention and, there were no significant differences in changes of these mediators between the AIT and the control group. Conclusions. A 12-week AIT intervention, although improving exercise capacity and endothelial function, did not attenuate serum inflammatory biomarkers in stable ischemic HF patients with an ICD on optimal medical therapy.

14.
Respir Med ; 152: 81-88, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31128615

RESUMO

BACKGROUND: COPD patients have an increased risk of developing lung cancer, but the underlying mechanisms are poorly understood. We aimed to identify risk factors for lung cancer in patients from the Bergen COPD Cohort Study. METHODS: We compared 433 COPD patients with 279 healthy controls, all former or current smokers. All COPD patients had FEV1<80% and FEV1/FVC-ratio<0.7. Baseline predictors were sex, age, spirometry, body composition, smoking history, emphysema assessed by CT, chronic bronchitis, prior exacerbation frequency, Charlson Comorbidity Score, inhalation medication and 44 serum/plasma inflammatory biomarkers. Patients were followed up for 9 years recording incidence of lung cancer. Cox-regression models were fitted for the statistical analyses. The biomarkers were evaluated using principal component analysis. RESULTS: 28 COPD patients and 3 controls developed lung cancer, COPD patients had a significantly higher risk of developing lung cancer, (HR 5.0; 95% CI 1.5-17.1, p < 0.01, adjusted values). Among COPD patients, emphysema (HR 4.4; 1.7-10.8, p < 0.01) and obesity (HR 3.3; 1.3-8.5, p = 0.02) were associated with a higher cancer rate. Use of inhaled steroids was associated with a lower rate (HR 0.4; 0.2-0.9, p = 0.03). Smoking status, pack-years smoked or levels of systemic inflammatory markers, except for interferon gamma-induced protein 10, did not affect the lung cancer rate in patients with COPD. CONCLUSION: Patients with COPD have a higher lung cancer rate compared to healthy controls adjusted for smoking. The presence of emphysema and obesity in COPD predicted a higher lung cancer risk in COPD patients. Systemic inflammation was not associated with increased lung cancer risk.

15.
J Infect Dis ; 2019 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-31077280

RESUMO

People with HIV (PWH) have an increased risk of cardiovascular disease (CVD) compared to the general population. In a nested case-control study of 55 PWH with first-time Myocardial Infarction (MI) (cases) and 182 PWH with no CVD (controls), we measured soluble markers of IL-1 activation at 4 different timepoints before the case´s MI. Cases had higher levels of IL-1Ra at all time-points leading up to first-time MI, and higher levels of IL-1Ra were associated with approximately 1.5-fold increased risk of MI, supporting the rationale to target IL-1 activation in order to reduce cardiovascular risk in PWH.

16.
BMJ Open ; 9(5): e030651, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31079089

RESUMO

OBJECTIVES: Patients with various inflammatory rheumatic diseases (IRDs) have increased risk of atherothrombotic disease. Lipoprotein (a) (Lp(a)) is a risk factor for atherosclerosis but its role in IRD with accompanying coronary artery disease (CAD) is still unclear. We aimed to examine if serum Lp(a) levels differed between CAD patients with and without accompanying IRD. DESIGN: A cross-sectional observational, patient-based cohort study. SETTING: Referred centre for coronary artery bypass grafting in the South Eastern part of Norway. PARTICIPANTS: 67 CAD patients with IRD (CAD/IRD) and 52 CAD patients without IRD (CAD/non-IRD). All patients were Caucasians, aged >18 years, without any clinically significant infection or malignancy. METHODS: Lp(a) levels in serum were analysed by particle enhanced immunoturbidimetric assay, and Lp(a) levels were related to clinical and biochemical characteristics of the patient population. RESULTS: We found no differences in serum levels of Lp(a) between CAD patients with and without IRD. In general, we found that Lp(a) correlated poorly with clinical and biochemical parameters including C reactive protein with the same pattern in the CAD/non-IRD and CAD/IRD groups. CONCLUSIONS: Our data do not support a link between inflammation and Lp(a) levels in CAD and in general Lp(a) levels were not correlated with other risk factors for cardiovascular disease.

17.
Eur Heart J Acute Cardiovasc Care ; : 2048872619846334, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31017470

RESUMO

AIMS: We investigated the dynamics, associations with patient characteristics, other biomarkers, and clinical outcomes of pentraxin 3 in acute coronary syndrome. METHODS AND RESULTS: In multivariate analyses, pentraxin 3 measured in 5154 patients randomised in the Platelet Inhibition and Patients Outcomes (PLATO) trial (NCT00391872) was compared with leukocytes, high-sensitivity C-reactive protein, interleukin-6, cystatin C, N-terminal prohormone brain natriuretic peptide, high-sensitivity troponin T and growth differentiation factor 15 concerning prediction of clinical outcome. Pentraxin 3 peaked earlier than high-sensitivity C-reactive protein and was more strongly correlated with N-terminal prohormone brain natriuretic peptide and high-sensitivity troponin T than with high-sensitivity C-reactive protein. The frequency of cardiovascular death, spontaneous myocardial infarction or stroke by quartiles of pentraxin 3 at admission was 6.1%, 7.3%, 9.7% and 10.7%, respectively ( p<0.0001). The hazard ratio per 50% increase of pentraxin 3 was 1.13 (95% confidence interval: 1.07-1.19), p<0.0001. This association remained significant after stepwise adjustments for leukocytes/high-sensitivity C-reactive protein (1.09 (1.02-1.15)), p=0.009, interleukin-6 (1.07 (1.01-1.14)), p=0.026, and cystatin C (1.07 (1.00-1.13)), p=0.044, but not after adjustment for N-terminal prohormone brain natriuretic peptide, high-sensitivity troponin T and growth differentiation factor 15. Admission pentraxin 3 was also associated with several of the individual endpoint components (cardiovascular death/spontaneous myocardial infarction; p=0.008, cardiovascular death; p=0.026, and spontaneous myocardial infarction; p=0.017), but not with stroke. Pentraxin 3 measured in the chronic phase (i.e. at one month) was still predictive of the composite endpoint in univariate analysis (1.12 (1.04-1.20) per 50% increase) p=0.0024, but not after adjustment for the other biomarkers. CONCLUSION: Admission level of pentraxin 3 is a modestly stronger predictor than high-sensitivity C-reactive protein and interleukin-6, but not than N-terminal prohormone brain natriuretic peptide or high-sensitivity troponin T, concerning cardiovascular outcome in acute coronary syndrome. Pentraxin 3 is more strongly correlated with N-terminal prohormone brain natriuretic peptide and high-sensitivity troponin T than with high-sensitivity C-reactive protein.

18.
Am J Physiol Lung Cell Mol Physiol ; 316(6): L999-L1012, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30908936

RESUMO

Lung diseases with hypoxia are complicated by pulmonary hypertension, leading to heart failure and death. No pharmacological treatment exists. Increased proinflammatory cytokines are found in hypoxic patients, suggesting an inflammatory pathogenesis. Caspase-1, the effector of the inflammasome, mediates inflammation through activation of the proinflammatory cytokines interleukin (IL)-18 and IL-1ß. Here, we investigate inflammasome-related mechanisms that can trigger hypoxia-induced pulmonary hypertension. Our aim was to examine whether caspase-1 induces development of hypoxia-related pulmonary hypertension and is a suitable target for therapy. Wild-type (WT) and caspase-1-/- mice were exposed to 10% oxygen for 14 days. Hypoxic caspase-1-/- mice showed lower pressure and reduced muscularization in pulmonary arteries, as well as reduced right ventricular remodeling compared with WT. Smooth muscle cell (SMC) proliferation was reduced in caspase-1-deficient pulmonary arteries and in WT arteries treated with a caspase-1 inhibitor. Impaired inflammation was shown in hypoxic caspase-1-/- mice by abolished pulmonary influx of immune cells and lower levels of IL-18, IL-1ß, and IL-6, which were also reduced in the medium surrounding caspase-1 abrogated pulmonary arteries. By adding IL-18 or IL-1ß to caspase-1-deficient pulmonary arteries, SMC proliferation was retained. Furthermore, inhibition of both IL-6 and phosphorylated STAT3 reduced proliferation of SMC in vitro, indicating IL-18, IL-6, and STAT3 as downstream mediators of caspase-1-induced SMC proliferation in pulmonary arteries. Caspase-1 induces SMC proliferation in pulmonary arteries through the caspase-1/IL-18/IL-6/STAT3 pathway, leading to pulmonary hypertension in mice exposed to hypoxia. We propose that caspase-1 inhibition is a potential target for treatment of pulmonary hypertension.

20.
Mol Nutr Food Res ; 63(7): e1800990, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30702198

RESUMO

SCOPE: Some studies suggest that a high dietary intake of omega-6 fatty acids is pro-inflammatory. However, whether omega-6 fatty acids actually cause pathogenic inflammation in humans is debated. Therefore, the associations between expression of immunology-related genes in peripheral blood mononuclear cells (PBMCs) and serum total omega-6 PUFA status are investigated. METHODS AND RESULTS: Serum fatty acid profile and expression of 460 immunology-related genes in PBMCs from 58 healthy children (6-13 years) is measured, and examined the expression differences between children with high or low total omega-6 PUFA status (upper vs lower tertile). Taken together, both univariate analyses and integrated omics analyses support that while high omega-6 PUFA level associated with higher expressing of genes related to innate immune responses, it also associated with lower expression of several genes related to adaptive immune responses. CONCLUSION: Omega-6 PUFA status associated both positively and negatively with expression of specific immunology-related genes in PBMCs in healthy children. The results may suggest a nuanced role for omega-6 fatty acids in the interphase of lipids and inflammation, and warrants further examination in gene-environment studies and randomized controlled trials.

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