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1.
Sci Rep ; 11(1): 19749, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611194

RESUMO

Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe-/- mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe-/-Neil3-/- mice and Apoe-/- mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe-/-Neil3-/- mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.

2.
BMC Infect Dis ; 21(1): 1073, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663245

RESUMO

BACKGROUND: Several inflammatory molecules participate in the immune response to malaria. Interleukin (IL)-18 is an inflammatory cytokine activated by NLRP3 inflammasomes. In clinical falciparum malaria, with and without HIV co-infection, data on IL-18 and in particular on its binding protein, IL-18bp, is scarce. METHODS: Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells using hemozoin crystals. RESULTS: (i) IL-18 and IL-18bp were markedly up-regulated during falciparum malaria with particular high levels in malaria patients co-infected with HIV and severe malaria disease. (ii) In the malaria group as a whole, both IL-18 and IL-18bp were positively correlated with disease severity, parasitemia, and endothelial cell activation as assessed by vWF in plasma. (iii) Whereas there was no change in IL-18 levels in malaria patients co-infected with HIV during follow-up, the patients with malaria only had slightly increased IL-18 levels. Further, the IL-18pb levels declined and thereby contributed to an increase in IL-18/IL-18bp ratio in all subgroups of malaria patients. (iv) IL-27, previously shown to be up-regulated in this malaria cohort, markedly induced a release of IL-18bp from endothelial cells in vitro, and notably, this presumably anti-inflammatory effect was counteracted by hemozoin. CONCLUSIONS: Our findings suggest that the IL-18 system could be an important mediator in the immune pathogenesis during falciparum malaria, potentially also representing a target for therapy.


Assuntos
Interleucina-18 , Malária , Células Endoteliais , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Parasitemia , Índice de Gravidade de Doença
3.
J Clin Immunol ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669143

RESUMO

PURPOSE: Fatty acid (FA) abnormalities are found in various inflammatory disorders and have been related to disturbed gut microbiota. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with altered gut microbial composition. We hypothesized that there is an altered FA profile in CVID patients, related to gut microbial dysbiosis. METHODS: Plasma FAs were measured in 39 CVID patients and 30 healthy controls. Gut microbial profile, a food frequency questionnaire, and the effect of the oral antibiotic rifaximin were investigated in CVID patients. RESULTS: The n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) (1.4 [1.0-1.8] vs. 1.9 [1.2-2.5], median (IQR), P < 0.05), and docosahexaenoic acid (DHA) (3.2 [2.4-3.9] vs. 3.5 [2.9-4.3], P < 0.05), all values expressed as weight percent of total plasma FAs, were reduced in CVID compared to controls. Also, n-6 PUFAs (34.3 ± 3.4 vs. 37.1 ± 2.8, mean ± SD, P < 0.001) and linoleic acid (LA) (24.5 ± 3.3 vs. 28.1 ± 2.7, P < 0.0001) and the FA anti-inflammatory index (98.9 [82.1-119.4] vs. 117.0 [88.7-153.1], median (IQR), P < 0.05) were reduced in CVID. The microbial alpha diversity was positively associated with plasma n-6 PUFAs (r = 0.41, P < 0.001) and LA (r = 0.51, P < 0.001), but not n-3 PUFAs (P = 0.78). Moreover, a 2-week course of rifaximin significantly reduced the proportion of n-6 PUFAs (P = 0.04, UNIANOVA). Serum immunoglobulin G (IgG) levels correlated with plasma n-3 PUFAs (rho = 0.36, P = 0.03) and DHA (rho = 0.41, P = 0.009). CONCLUSION: We found a potentially unfavorable FA profile in CVID, related to low IgG levels. High plasma n-6 PUFAs were related to increased gut microbial diversity and altered by rifaximin therapy.

4.
J Intern Med ; 290(5): 1083-1097, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34506681

RESUMO

BACKGROUND: The functional status of lipoprotein particles contributes to atherogenesis. The tendency of plasma low-density lipoprotein (LDL) particles to aggregate and the ability of igh-density lipoprotein (HDL) particles to induce and mediate reverse cholesterol transport associate with high and low risk for cardiovascular disease in adult patients, respectively. However, it is unknown whether children with familial hypercholesterolemia (FH) display lipoprotein function alterations. HYPOTHESIS: We hypothesized that FH children had disrupted lipoprotein functions. METHODS: We analyzed LDL aggregation susceptibility and HDL-apoA-I exchange (HAE), and activity of four proteins that regulate lipoprotein metabolism (cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, phospholipid transfer protein, and paraoxonase-1) in plasma samples derived from children with FH (n = 47) and from normocholesterolemic children (n = 56). Variation in lipoprotein functions was further explored using an nuclear magnetic resonance-based metabolomics profiling approach. RESULTS: LDL aggregation was higher, and HAE was lower in FH children than in normocholesterolemic children. LDL aggregation associated positively with LDL cholesterol (LDL-C) and negatively with triglycerides, and HAE/apoA-I associated negatively with LDL-C. Generally, the metabolomic profile for LDL aggregation was opposite of that of HAE/apoA-I. CONCLUSIONS: FH children displayed increased atherogenicity of LDL and disrupted HDL function. These newly observed functional alterations in LDL and HDL add further understanding of the risk for atherosclerotic cardiovascular disease in FH children.

5.
Eur Heart J ; 42(39): 4064-4072, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34405870

RESUMO

AIMS: We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7-10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients. METHODS AND RESULTS: We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase-DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits. CONCLUSIONS: The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.


Assuntos
COVID-19 , Trombocitopenia , Vacinas , Complexo Antígeno-Anticorpo , Vacinas contra COVID-19 , Humanos , Imunidade Inata , SARS-CoV-2
7.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343089

RESUMO

Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.


Assuntos
Reparo do DNA , DNA Mitocondrial/metabolismo , Cardiopatias/fisiopatologia , Coração/fisiopatologia , Miocárdio/metabolismo , NAD/metabolismo , Animais , Dano ao DNA , Células HeLa , Humanos , Camundongos , Mitocôndrias/metabolismo , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Compostos de Piridínio/efeitos adversos , Sirtuínas/antagonistas & inibidores
8.
EBioMedicine ; 70: 103511, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34329947

RESUMO

BACKGROUND: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). METHODS: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis. FINDINGS: We enrolled a total of 151 patients. After three months' treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein. INTERPRETATION: Three months' treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF. FUNDING: The trial was funded by the Norwegian Association for Public Health, the Blix foundation, Stein Erik Hagen's Foundation for Clinical Heart Research, Ada og Hagbart Waages humanitære og veldedige stiftelse, Alfasigma, and Biocodex.

9.
J Am Heart Assoc ; 10(14): e020656, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34259011

RESUMO

Background In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine-to-inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine-to-inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine-ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E-deficient (ApoE-/-) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE-/- mice. Conclusions ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.


Assuntos
Aorta Torácica/patologia , Aterosclerose/genética , Quimiocina CCL2/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Regulação da Expressão Gênica , Monócitos/metabolismo , RNA/genética , Idoso , Animais , Aorta Torácica/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Quimiocina CCL2/biossíntese , Citocinas , Desoxirribonuclease (Dímero de Pirimidina)/biossíntese , Modelos Animais de Doenças , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Estudos Retrospectivos
10.
Atherosclerosis ; 324: 123-132, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33714552

RESUMO

BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.


Assuntos
Aterosclerose , DNA Glicosilases , Miócitos de Músculo Liso/enzimologia , Placa Aterosclerótica , Animais , Aterosclerose/genética , Proliferação de Células , Células Cultivadas , DNA Glicosilases/genética , Endodesoxirribonucleases , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/citologia , N-Glicosil Hidrolases , Fenótipo
11.
J Allergy Clin Immunol ; 147(1): 92-98, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971109

RESUMO

BACKGROUND: The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. OBJECTIVE: We examined the parameters of activation of different leukocyte subsets in COVID-19-infected patients in relation to disease severity. METHODS: We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19-infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. RESULTS: Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B-type natriuretic peptide. CONCLUSION: Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell-targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.


Assuntos
COVID-19/sangue , Receptor Celular 2 do Vírus da Hepatite A/sangue , SARS-CoV-2/metabolismo , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Receptores de Lipopolissacarídeos/sangue , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/sangue , Índice de Gravidade de Doença , Linfócitos T/metabolismo , Fatores de Tempo
12.
J Clin Lipidol ; 15(1): 134-141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33358307

RESUMO

BACKGROUND: Reduction of the aortic valve area (AVA) may lead to aortic valve stenosis with considerable impact on morbidity and mortality if not identified and treated. Lipoprotein (a) [Lp(a)] and also inflammatory biomarkers, including platelet derived biomarkers, have been considered risk factor for aortic stenosis; however, the association between Lp(a), inflammatory biomarkers and AVA among patients with familial hypercholesterolemia (FH) is not clear. OBJECTIVE: We aimed to investigate the relation between concentration of Lp(a), measurements of the aortic valve including velocities and valve area and circulating inflammatory biomarkers in adult FH subjects and controls. METHODS: In this cross-sectional study aortic valve measures were examined by cardiac ultrasound and inflammatory markers were analyzed in non-fasting blood samples. The study participants were 64 FH subjects with high (n = 29) or low (n = 35) Lp(a), and 14 healthy controls. RESULTS: Aortic valve peak velocity was higher (p = 0.02), and AVA was lower (p = 0.04) in the FH patients compared to controls; however, when performing multivariable linear regression, there were no significant differences. Furthermore, there were no significant differences between the high and low FH Lp(a) groups regarding the aortic valve. FH subjects had higher levels of platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to controls (0.003 ≤ P ≤ 0.03). This result persisted after multiple linear regression. CONCLUSIONS: Middle-aged, intensively treated FH subjects have higher aortic valve velocity, lower AVA, and higher levels of the platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to healthy control subjects. The aortic valve findings were not significant after multiple linear regression, whereas the higher levels of platelet-derived markers were maintained.


Assuntos
Hiperlipoproteinemia Tipo II , Adulto , Biomarcadores , Humanos , Pessoa de Meia-Idade
13.
Sci Rep ; 10(1): 21006, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273482

RESUMO

Obesity-related diseases (e.g. type 2 diabetes mellitus and cardiovascular disorders) represent an increasing health problem worldwide. NLRP3 inflammasome activation may underlie obesity-induced inflammation and insulin resistance, and NLRP3 deficient mice exposed to high fat diet (HFD) appear to be protected from left ventricle (LV) concentric remodeling. Herein, we investigated if these beneficial effects were associated with alterations in plasma metabolites, using metabolomic and lipidomic analysis, and gut microbiota composition, using 16S rRNA sequencing of cecum content, comparing NLRP3 deficient and wild type (WT) mice on HFD and control diet. Obese NLRP3 deficient mice had lower systemic ceramide levels, potentially resulting attenuating inflammation, altered hepatic expression of fatty acids (FA) with lower mono-saturated FA and higher polyunsaturated FA levels, potentially counteracting development of liver steatosis, downregulated myocardial energy metabolism as assessed by proteomic analyses of LV heart tissue, and different levels of bile acids as compared with WT mice. These changes were accompanied by an altered composition of gut microbiota associated with decreased systemic levels of tri-methylamine-N-oxide and lipopolysaccharide, potentially inducing attenuating systemic inflammation and beneficial effects on lipid metabolism. Our findings support a role of NLRP3 inflammasome in the interface between metabolic and inflammatory stress, involving an altered gut microbiota composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal , Metaboloma , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Ceramidas/sangue , Metabolismo Energético , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Lipopolissacarídeos/sangue , Fígado/metabolismo , Masculino , Metilaminas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
14.
Front Immunol ; 11: 574500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042155

RESUMO

A substantial proportion of patients with common variable immunodeficiency (CVID) have inflammatory and autoimmune complications of unknown etiology. We have previously shown that systemic inflammation in CVID correlates with their gut microbial dysbiosis. The gut microbiota dependent metabolite trimethylamine N-oxide (TMAO) has been linked to several metabolic and inflammatory disorders, but has hitherto not been investigated in relation to CVID. We hypothesized that TMAO is involved in systemic inflammation in CVID. To explore this, we measured plasma concentrations of TMAO, inflammatory markers, and lipopolysaccharide (LPS) in 104 CVID patients and 30 controls. Gut microbiota profiles and the bacterial genes CutC and CntA, which encode enzymes that can convert dietary metabolites to trimethylamine in the colon, were examined in fecal samples from 40 CVID patients and 86 controls. Furthermore, a food frequency questionnaire and the effect of oral antibiotic rifaximin on plasma TMAO concentrations were explored in these 40 patients. We found CVID patients to have higher plasma concentrations of TMAO than controls (TMAO 5.0 [2.9-8.6] vs. 3.2 [2.2-6.3], p = 0.022, median with IQR). The TMAO concentration correlated positively with tumor necrosis factor (p = 0.008, rho = 0.26), interleukin-12 (p = 0.012, rho = 0.25) and LPS (p = 0.034, rho = 0.21). Dietary intake of meat (p = 0.678), fish (p = 0.715), egg (p = 0.138), dairy products (p = 0.284), and fiber (p = 0.767) did not significantly impact on the TMAO concentrations in plasma, nor did a 2-week course of the oral antibiotic rifaximin (p = 0.975). However, plasma TMAO concentrations correlated positively with gut microbial abundance of Gammaproteobacteria (p = 0.021, rho = 0.36). Bacterial gene CntA was present in significantly more CVID samples (75%) than controls (53%), p = 0.020, potentially related to the increased abundance of Gammaproteobacteria in these samples. The current study demonstrates that elevated TMAO concentrations are associated with systemic inflammation and increased gut microbial abundance of Gammaproteobacteria in CVID patients, suggesting that TMAO could be a link between gut microbial dysbiosis and systemic inflammation. Gut microbiota composition could thus be a potential therapeutic target to reduce systemic inflammation in CVID.


Assuntos
Imunodeficiência de Variável Comum/sangue , Microbioma Gastrointestinal , Metilaminas/sangue , Adulto , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biomarcadores/sangue , Carnitina/metabolismo , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/microbiologia , Dieta , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Humanos , Imunoglobulina A Secretora/sangue , Inflamação , Lipopolissacarídeos/sangue , Masculino , Redes e Vias Metabólicas , Metilaminas/metabolismo , Pessoa de Meia-Idade , Rifaximina/administração & dosagem
15.
Biochem Biophys Res Commun ; 533(4): 631-637, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33004177

RESUMO

BACKGROUND: More than 170 post-transcriptional RNA modifications regulate the localization, processing and function of cellular RNAs, and aberrant RNA modifications have been linked to a range of human diseases. The RNA modification landscape in atherosclerosis, the main underlying cause of cardiovascular diseases, is still largely unknown. METHODS: We used mass spectrometry to analyse a selection of RNA-modifying enzymes and the N6-methyladenosine (m6A) in carotid atherosclerotic lesion samples representing early and advanced stages of atherosclerosis as compared to non-atherosclerotic arteries from healthy controls. FINDINGS: (i) the detection of different levels of several enzymes involved in methylations occurring in rRNA and mRNA; (ii) these findings included changes in the levels of methyltransferases ('writers'), binding proteins ('readers') and demethylases ('erasers') during atherosclerosis as compared to non-atherosclerotic control arteries, with generally the most prominent differences in samples from early atherosclerotic lesions; and (iii) these changes were accompanied by a marked downregulation of m6A in rRNA, the most abundant and well-studied modification in mRNA with a wide range of effects on cell biology. INTERPRETATION: We show for the first time that RNA-modifying enzymes and the well-studied RNA modification m6A are differentially regulated in atherosclerotic lesions, which potentially could help creating new prognostic and treatment strategies.


Assuntos
Adenosina/análogos & derivados , Doenças das Artérias Carótidas/metabolismo , Metiltransferases/metabolismo , Placa Aterosclerótica/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , RNA Ribossômico/metabolismo , Adenosina/análise , Adenosina/metabolismo , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/genética , Cromatografia Líquida , Humanos , Metilação , Oxirredutases N-Desmetilantes/metabolismo , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/genética , Espectrometria de Massas em Tandem
16.
Circ Heart Fail ; 13(10): e006643, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32962417

RESUMO

BACKGROUND: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS. METHODS: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed. RESULTS: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, P<0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], P<0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice). CONCLUSIONS: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.


Assuntos
Estenose da Valva Aórtica/sangue , Valva Aórtica/metabolismo , Proteína 1 Semelhante à Quitinase-3/sangue , Idoso , Idoso de 80 Anos ou mais , Animais , Valva Aórtica/patologia , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/mortalidade , Biomarcadores/sangue , Estudos de Casos e Controles , Proteína 1 Semelhante à Quitinase-3/genética , Estudos Transversais , Dinamarca , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa2 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Noruega , Prognóstico , Índice de Gravidade de Doença , Regulação para Cima
17.
EBioMedicine ; 60: 102985, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32927275

RESUMO

BACKGROUND: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease. METHODS: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling. FINDINGS: Transcripts of interleukin (IL)-1beta(ß) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1ß protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1ß, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components. INTERPRETATION: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.


Assuntos
Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/metabolismo , Colesterol/metabolismo , Proteínas do Sistema Complemento/imunologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Doenças das Artérias Carótidas/patologia , Complemento C5a/imunologia , Biologia Computacional/métodos , Doença da Artéria Coronariana/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Cristais Líquidos , Placa Aterosclerótica
18.
Proc Natl Acad Sci U S A ; 117(40): 25018-25025, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32943538

RESUMO

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.


Assuntos
Betacoronavirus/imunologia , Ativação do Complemento , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Insuficiência Respiratória/imunologia , Idoso , Biomarcadores/sangue , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Insuficiência Respiratória/virologia , SARS-CoV-2 , Carga Viral
19.
J Am Heart Assoc ; 9(17): e016360, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32809893

RESUMO

Background The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. Methods and Results Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow-up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04-1.21), P=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02-1.19; P=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44-0.88; P=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37-0.88; P=0.0114). Conclusions Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00391872.


Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Aterosclerose/sangue , Cisteína Endopeptidases/sangue , Síndrome Coronariana Aguda/complicações , Idoso , Aterosclerose/metabolismo , Estudos de Casos e Controles , Clopidogrel/uso terapêutico , Cisteína Proteases/sangue , Morte , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/fisiopatologia , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia , Ticagrelor/uso terapêutico , Resultado do Tratamento
20.
Scand Cardiovasc J ; 54(5): 274-279, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32500743

RESUMO

Objectives. Inflammatory responses are closely knit with low-density lipoprotein (LDL)-cholesterol in driving atherosclerosis. Even if LDL-cholesterol is causative to atherosclerotic diseases and LDL-cholesterol lowering reduces hard clinical endpoints, there is a residual risk for clinical events, possibly driven by inflammatory processes, in accordance with its role in autoimmune diseases. Design. As LDL-cholesterol treatment targets are reduced, the use of non-statin lipid-lowering drugs will probably increase. Atherosclerotic plaques evolve through lipid infiltration and modification in the intima, furthermore infiltration of cells including monocytes, macrophages, T-lymphocytes and neutrophils initiating inflammatory signaling. Here we briefly review inflammation in atherosclerosis and the effects of the non-statin lipid-lowering drugs on inflammation. The review is limited to the most common non-statin lipid lowering drugs, i.e. proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, bile acid sequestrants (BAS) and cholesterol absorption inhibitors. Results. PCSK9 inhibition is mostly studied together with statins and is associated with a reduction of pro-inflammatory cytokines. Furthermore, PCSK9 inhibitors seem to have an effect on monocyte migration trough CCR2. They also have an interaction with sirtuins, possibly offering a therapeutic target. BAS have several interesting effects on inflammation, including reduction of pro-inflammatory cytokines and a reduction of the number of infiltrating macrophages, however there are relatively few reports considering that these drugs have been on the market for decades. Ezetimibe also has effects on inflammation including reduction of pro-inflammatory cytokines and adhesion molecules, however these effects are usually accomplished in tandem with statins. Conclusion. This topic adds an interesting piece to the puzzle of atherosclerosis, indicating that PCSK9 inhibition, BAS and ezetimibe all affect thromboinflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Mediadores da Inflamação/sangue , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/diagnóstico , Biomarcadores/sangue , Regulação para Baixo , Humanos , Inflamação/sangue , Inflamação/diagnóstico
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