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1.
Cell Mol Life Sci ; 79(10): 512, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36094626

RESUMO

To fulfil its orchestration of immune cell trafficking, a network of chemokines and receptors developed that capitalizes on specificity, redundancy, and functional selectivity. The discovery of heteromeric interactions in the chemokine interactome has expanded the complexity within this network. Moreover, some inflammatory mediators, not structurally linked to classical chemokines, bind to chemokine receptors and behave as atypical chemokines (ACKs). We identified macrophage migration inhibitory factor (MIF) as an ACK that binds to chemokine receptors CXCR2 and CXCR4 to promote atherogenic leukocyte recruitment. Here, we hypothesized that chemokine-chemokine interactions extend to ACKs and that MIF forms heterocomplexes with classical chemokines. We tested this hypothesis by using an unbiased chemokine protein array. Platelet chemokine CXCL4L1 (but not its variant CXCL4 or the CXCR2/CXCR4 ligands CXCL8 or CXCL12) was identified as a candidate interactor. MIF/CXCL4L1 complexation was verified by co-immunoprecipitation, surface plasmon-resonance analysis, and microscale thermophoresis, also establishing high-affinity binding. We next determined whether heterocomplex formation modulates inflammatory/atherogenic activities of MIF. Complex formation was observed to inhibit MIF-elicited T-cell chemotaxis as assessed by transwell migration assay and in a 3D-matrix-based live cell-imaging set-up. Heterocomplexation also blocked MIF-triggered migration of microglia in cortical cultures in situ, as well as MIF-mediated monocyte adhesion on aortic endothelial cell monolayers under flow stress conditions. Of note, CXCL4L1 blocked binding of Alexa-MIF to a soluble surrogate of CXCR4 and co-incubation with CXCL4L1 attenuated MIF responses in HEK293-CXCR4 transfectants, indicating that complex formation interferes with MIF/CXCR4 pathways. Because MIF and CXCL4L1 are platelet-derived products, we finally tested their role in platelet activation. Multi-photon microscopy, FLIM-FRET, and proximity-ligation assay visualized heterocomplexes in platelet aggregates and in clinical human thrombus sections obtained from peripheral artery disease (PAD) in patients undergoing thrombectomy. Moreover, heterocomplexes inhibited MIF-stimulated thrombus formation under flow and skewed the lamellipodia phenotype of adhering platelets. Our study establishes a novel molecular interaction that adds to the complexity of the chemokine interactome and chemokine/receptor-network. MIF/CXCL4L1, or more generally, ACK/CXC-motif chemokine heterocomplexes may be target structures that can be exploited to modulate inflammation and thrombosis.


Assuntos
Aterosclerose , Fatores Inibidores da Migração de Macrófagos , Trombose , Aterosclerose/metabolismo , Células HEK293 , Humanos , Inflamação/metabolismo , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fator Plaquetário 4 , Receptores de Interleucina-8B/química , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo
2.
Clin Cardiol ; 45(9): 943-951, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35789499

RESUMO

BACKGROUND: Cardiovascular risk factors and comorbidities are highly prevalent among COVID-19 patients and are associated with worse outcomes. HYPOTHESIS: We therefore investigated if established cardiovascular risk assessment models could efficiently predict adverse outcomes in COVID-19. Furthermore, we aimed to generate novel risk scores including various cardiovascular parameters for prediction of short- and midterm outcomes in COVID-19. METHODS: We included 441 consecutive patients diagnosed with SARS-CoV-2 infection. Patients were followed-up for 30 days after the hospital admission for all-cause mortality (ACM), venous/arterial thromboembolism, and mechanical ventilation. We further followed up the patients for post-COVID-19 syndrome for 6 months and occurrence of myocarditis, heart failure, acute coronary syndrome (ACS), and rhythm events in a 12-month follow-up. Discrimination performance of DAPT, GRACE 2.0, PARIS-CTE, PREDICT-STABLE, CHA2-DS2-VASc, HAS-BLED, PARIS-MB, PRECISE-DAPT scores for selected endpoints was evaluated by ROC-analysis. RESULTS: Out of established risk assessment models, GRACE 2.0 score performed best in predicting combined endpoint and ACM. Risk assessment models including age, cardiovascular risk factors, echocardiographic parameters, and biomarkers, were generated and could successfully predict the combined endpoint, ACM, venous/arterial thromboembolism, need for mechanical ventilation, myocarditis, ACS, heart failure, and rhythm events. Prediction of post-COVID-19 syndrome was poor. CONCLUSION: Risk assessment models including age, laboratory parameters, cardiovascular risk factors, and echocardiographic parameters showed good discrimination performance for adverse short- and midterm outcomes in COVID-19 and outweighed discrimination performance of established cardiovascular risk assessment models.


Assuntos
Síndrome Coronariana Aguda , COVID-19 , Insuficiência Cardíaca , Miocardite , Tromboembolia , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/epidemiologia , COVID-19/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Inibidores da Agregação Plaquetária , Prognóstico , Medição de Risco , Fatores de Risco , SARS-CoV-2 , Síndrome de COVID-19 Pós-Aguda
3.
Cardiovasc Res ; 118(8): 1904-1916, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34323932

RESUMO

AIMS: Platelets play a key role in the pathophysiology of coronary artery disease (CAD) and patients with enhanced platelet activation are at increased risk to develop adverse cardiovascular events. Beyond reliable cardiovascular risk factors such as dyslipoproteinaemia, significant changes of platelet lipids occur in patients with CAD. In this study, we investigate the platelet lipidome by untargeted liquid chromatography-mass spectrometry, highlighting significant changes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. Additionally, we classify the platelet lipidome, spotlighting specific glycerophospholipids as key players in ACS patients. Furthermore, we examine the impact of significantly altered lipids in ACS on platelet-dependent thrombus formation and aggregation. METHODS AND RESULTS: In this consecutive study, we characterized the platelet lipidome in a CAD cohort (n = 139) and showed significant changes of lipids between patients with ACS and CCS. We found that among 928 lipids, 7 platelet glycerophospholipids were significantly up-regulated in ACS, whereas 25 lipids were down-regulated compared to CCS. The most prominent up-regulated lipid in ACS, PC18:0 (PC 10:0-8:0), promoted platelet activation and ex vivo platelet-dependent thrombus formation. CONCLUSIONS: Our results reveal that the platelet lipidome is altered in ACS and up-regulated lipids embody primarily glycerophospholipids. Alterations of the platelet lipidome, especially of medium chain lipids, may play a role in the pathophysiology of ACS.


Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Trombose , Plaquetas , Glicerofosfolipídeos , Humanos , Lipidômica , Lipídeos
4.
Int J Mol Sci ; 23(1)2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-35008437

RESUMO

Traditional antithrombotic agents commonly share a therapy-limiting side effect, as they increase the overall systemic bleeding risk. A novel approach for targeted antithrombotic therapy is nanoparticles. In other therapeutic fields, nanoparticles have enabled site-specific delivery with low levels of toxicity and side effects. Here, we paired nanotechnology with an established dimeric glycoprotein VI-Fc (GPVI-Fc) and a GPVI-CD39 fusion protein, thereby combining site-specific delivery and new antithrombotic drugs. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, NP-BSA, NP-GPVI and NP-GPVI-CD39 were characterized through electron microscopy, atomic force measurements and flow cytometry. Light transmission aggregometry enabled analysis of platelet aggregation. Thrombus formation was observed through flow chamber experiments. NP-GPVI and NP-GPVI-CD39 displayed a characteristic surface coating pattern. Fluorescence properties were identical amongst all samples. NP-GPVI and NP-GPVI-CD39 significantly impaired platelet aggregation. Thrombus formation was significantly impaired by NP-GPVI and was particularly impaired by NP-GPVI-CD39. The receptor-coated nanoparticles NP-GPVI and the bifunctional molecule NP-GPVI-CD39 demonstrated significant inhibition of in vitro thrombus formation. Consequently, the nanoparticle-mediated antithrombotic effect of GPVI-Fc, as well as GPVI-CD39, and an additive impact of CD39 was confirmed. In conclusion, NP-GPVI and NP-GPVI-CD39 may serve as a promising foundation for a novel therapeutic approach regarding targeted antithrombotic therapy.


Assuntos
Antígenos CD/metabolismo , Apirase/metabolismo , Fibrinolíticos/farmacologia , Fragmentos Fc das Imunoglobulinas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Citometria de Fluxo , Humanos , Técnicas In Vitro , Microscopia Eletrônica , Modelos Biológicos , Nanopartículas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
5.
J Breath Res ; 14(4): 041003, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33006317

RESUMO

We hypothesized that most patients with severe pulmonary COVID-19 were exposed to cough aerosols. Among patients that were almost 100% certain which person infected them, only 14 out of 38 overall, and 9 out of 25 hospitalized patients requiring supplemental oxygen, were infected by someone who coughed, which did not support our hypothesis. Talking, especially with a loud voice, could be an alternative source generating SARS-CoV-2 aerosols. Further research is needed to determine how SARS-CoV-2 spreads. Avoiding to talk when you are not wearing your mask and not talking with a loud voice, 'voice etiquette', could be other public health interventions worthwhile exploring.


Assuntos
Aerossóis , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/etiologia , Tosse/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/etiologia , Betacoronavirus , COVID-19 , Humanos , Pandemias , SARS-CoV-2
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