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1.
Cells ; 10(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477776

RESUMO

Endotheliopathy is suggested to be an important feature of COVID-19 in hospitalized patients. To determine whether endotheliopathy is involved in COVID-19-associated mortality, markers of endothelial damage were assessed in critically ill COVID-19 patients upon intensive care unit (ICU) admission. Thirty-eight critically ill COVID-19 patients were included in this observational study, 10 of whom died in the ICU. Endothelial biomarkers, including soluble (s)E-selectin, sP-selectin, angiopoietin 1 and 2 (Ang-1 and Ang-2, respectively), soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), soluble vascular endothelial (VE)-cadherin, and von Willebrand factor (vWf), were measured upon ICU admission. The ICU cohort was subsequently divided into survivors and non-survivors; Kaplan-Meier analysis was used to explore associations between biomarkers and survival, while receiver operating characteristic (ROC) curves were generated to determine their potential prognostic value. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were significantly elevated in ICU non-survivors compared to survivors, and also associated with a higher mortality probability in the Kaplan-Meier analysis. The prognostic values of sE-selectin, Ang-2, and sICAM-1 from the generated ROC curves were greater than 0.85. Hence, we conclude that in our cohort, ICU non-survivors had higher levels of specific endothelial markers compared to survivors. Elevated levels of these markers upon ICU admission could possibly predict mortality in COVID-19.


Assuntos
/complicações , Endotélio Vascular/patologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Estado Terminal , Endotélio Vascular/virologia , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico
3.
Med Hypotheses ; 146: 110412, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33308936

RESUMO

The Corona Virus Disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) requires a rapid solution and global collaborative efforts in order to define preventive and treatment strategies. One of the major challenges of this disease is the high number of patients needing advanced respiratory support due to the Acute Respiratory Distress Syndrome (ARDS) as the lung is the major - although not exclusive - target of the virus. The molecular mechanisms, pathogenic drivers and the target cell type(s) in SARS-CoV-2 infection are still poorly understood, but the development of a "hyperactive" immune response is proposed to play a role in the evolution of the disease and it is envisioned as a major cause of morbidity and mortality. Here we propose a theory by which the main targets for SARS-CoV-2 are the Type II Alveolar Epithelial Cells and the clinical manifestations of the syndrome are a direct consequence of their involvement. We propose the existence of a vicious cycle by which once alveolar damage starts in AEC II cells, the inflammatory state is supported by macrophage pro-inflammatory polarization (M1), cytokines release and by the activation of the NF-κB pathway. If this theory is confirmed, future therapeutic efforts can be directed to target Type 2 alveolar cells and the molecular pathogenic drivers associated with their dysfunction with currently available therapeutic strategies.


Assuntos
Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/virologia , /virologia , Modelos Biológicos , NF-kappa B/imunologia , Células Epiteliais Alveolares/patologia , /etiologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Inflamação/imunologia , Inflamação/patologia , Ventilação Líquida , Macrófagos/imunologia , Macrófagos/patologia , NF-kappa B/antagonistas & inibidores , Neutrófilos/imunologia , Neutrófilos/patologia , Pandemias , Surfactantes Pulmonares/uso terapêutico , /imunologia , /imunologia , Transdução de Sinais/imunologia
4.
J Surg Res ; 257: 178-188, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32835951

RESUMO

Cardiac surgery, including cardioplegic arrest and extracorporeal circulation, causes endothelial dysfunction, which can lead to no-reflow phenomenon and reduction of myocardial pump function. Nitric oxide (NO) deficiency is involved in this pathologic process, thereby providing a fundamental basis for the use of NO replacement therapy. Presently used drugs and additives to cardioplegic and heart preservation solutions are not able to reliably protect endothelial cells and cardiomyocytes from ischemia-reperfusion injury. This review discusses promising NO-releasing compounds of various chemical classes for cardioplegia and reperfusion, which effectively maintain NO homeostasis under experimental conditions, and presents the mechanisms of their action on the cardiovascular system. Incomplete preclinical studies and a lack of toxicity assessment, however, hinder translation of these drug candidates into the clinic. Perspectives for modulation of endothelial function using NO-mediated mechanisms are discussed. They are based on the cardioprotective potential of targeting vascular gap junctions and endothelial ion channels, intracoronary administration of progenitor cells, and endothelial-specific microRNAs. Some of these strategies may provide important therapeutic benefits for human cardiovascular interventions.


Assuntos
Cardiotônicos/farmacologia , Parada Cardíaca Induzida/efeitos adversos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/metabolismo , Animais , Cardiotônicos/uso terapêutico , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Junções Comunicantes/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Canais Iônicos/metabolismo , MicroRNAs/uso terapêutico , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Óxido Nítrico/agonistas , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Transplante de Células-Tronco/métodos
5.
J Surg Res ; 257: 294-305, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871430

RESUMO

BACKGROUND: Drug-eluting stents impair post-angioplasty re-endothelialization thus compromising restenosis prevention while heightening thrombotic risks. We recently found that inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) effectively mitigated both restenosis and thrombosis in rodent models. This motivated us to determine how PERK inhibition impacts re-endothelialization. METHODS: Re-endothelialization was evaluated in endothelial-denuded rat carotid arteries after balloon angioplasty and periadventitial administration of PERK inhibitor in a hydrogel. To study whether PERK in smooth muscle cells (SMCs) regulates re-endothelialization by paracrinally influencing endothelial cells (ECs), denuded arteries exposing SMCs were lentiviral-infected to silence PERK; in vitro, the extracellular vesicles isolated from the medium of PDGF-activated, PERK-upregulating human primary SMCs were transferred to human primary ECs. RESULTS: Treatment with PERK inhibitor versus vehicle control accelerated re-endothelialization in denuded arteries. PERK-specific silencing in the denuded arterial wall (mainly SMCs) also enhanced re-endothelialization compared to scrambled shRNA control. In vitro, while medium transfer from PDGF-activated SMCs impaired EC viability and increased the mRNA levels of dysfunctional EC markers, either PERK inhibition or silencing in donor SMCs mitigated these EC changes. Furthermore, CXCL10, a paracrine cytokine detrimental to ECs, was increased by PDGF activation and decreased after PERK inhibition or silencing in SMCs. CONCLUSIONS: Attenuating PERK activity pharmacologically or genetically provides an approach to accelerating post-angioplasty re-endothelialization in rats. The mechanism may involve paracrine factors regulated by PERK in SMCs that impact neighboring ECs. This study rationalizes future development of PERK-targeted endothelium-friendly vascular interventions.


Assuntos
Angioplastia com Balão/efeitos adversos , Reestenose Coronária/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Reepitelização/efeitos dos fármacos , eIF-2 Quinase/antagonistas & inibidores , Angioplastia com Balão/instrumentação , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Reestenose Coronária/etiologia , Modelos Animais de Doenças , Stents Farmacológicos/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/genética , RNA Interferente Pequeno/metabolismo , Ratos , Reepitelização/genética , eIF-2 Quinase/genética
6.
J Immunoassay Immunochem ; 41(6): 1000-1009, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33353460

RESUMO

Autopsies represent medical procedures through which the causes of patients' deaths are determined or, through tissue sampling and microscopic examination of slides in usual stains or special tests, one can offer the basis for understanding the physiopathological mechanisms that contribute to the patients' death Histological findings of tissue samples from patients who have died of COVID-19 have been mainly orientated to lung, heart, liver, kidney damage with a small percent of them following other organs, but none has, to our knowledge, studied skeletal muscle.


Assuntos
/patologia , Músculo Esquelético/patologia , Músculo Esquelético/virologia , Necrose , Autopsia , Creatina Quinase/sangue , Endotélio Vascular/patologia , Evolução Fatal , Humanos , Inflamação , Isquemia/patologia , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/imunologia , Distribuição Tecidual
7.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352699

RESUMO

The new coronavirus disease-2019 (COVID-19), which is spreading around the world and threatening people, is easily infecting a large number of people through airborne droplets; moreover, patients with hypertension, diabetes, obesity, and cardiovascular disease are more likely to experience severe conditions. Vascular endothelial dysfunction has been suggested as a common feature of high-risk patients prone to severe COVID-19, and measurement of vascular endothelial function may be recommended for predicting severe conditions in high-risk patients with COVID-19. However, fragmented vascular endothelial glycocalyx (VEGLX) is elevated in COVID-19 patients, suggesting that it may be useful as a prognostic indicator. Although the relationship between VEGLX and severe acute respiratory syndrome coronavirus 2 infections has not been well studied, some investigations into COVID-19 have clarified the relationship between VEGLX and the mechanism that leads to severe conditions. Clarifying the usefulness of VEGLX assessment as a predictive indicator of the development of severe complications is important as a strategy for confronting pandemics caused by new viruses with a high affinity for the vascular endothelium that may recur in the future.


Assuntos
/patologia , Endotélio Vascular/patologia , Glicocálix/patologia , Doenças Vasculares/patologia , Células Endoteliais/patologia , Humanos , Pulmão/patologia , Pulmão/virologia , Prognóstico , Doenças Vasculares/virologia
8.
Mol Med Rep ; 22(6): 4485-4491, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173966

RESUMO

In December 2019, an emergence of pneumonia was detected in patients infected with a novel coronavirus (CoV) in Wuhan (Hubei, China). The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome­CoV­2 and the disease CoV disease­19 (COVID­19). Patients with COVID­19 present with symptoms associated with respiratory system dysfunction and hematological changes, including lymphopenia, thrombocytopenia and coagulation disorders. However, to the best of our knowledge, the pathogenesis of COVID­19 remains unclear. Therefore, understanding the mechanisms underlying the hematological changes that manifest during COVID­19 may aid in the development of treatments and may improve patient prognosis.


Assuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Microambiente Celular , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Testes Diagnósticos de Rotina , Endotélio Vascular/patologia , Testes Hematológicos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Hipoalbuminemia/etiologia , Fígado/fisiopatologia , Pulmão/fisiopatologia , Linfopenia/etiologia , Linfopenia/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/terapia , Traumatismo por Reperfusão/etiologia , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia , Trombofilia/etiologia
9.
Am J Physiol Heart Circ Physiol ; 319(6): H1181-H1196, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035434

RESUMO

Extracellular vesicles (EVs) have attracted rising interests in the cardiovascular field not only because they serve as serological markers for circulatory disorders but also because they participate in important physiological responses to stress and inflammation. In the circulation, these membranous vesicles are mainly derived from blood or vascular cells, and they carry cargos with distinct molecular signatures reflecting the origin and activation state of parent cells that produce them, thus providing a powerful tool for diagnosis and prognosis of pathological conditions. Functionally, circulating EVs mediate tissue-tissue communication by transporting bioactive cargos to local and distant sites, where they directly interact with target cells to alter their function. Recent evidence points to the critical contributions of EVs to the pathogenesis of vascular endothelial barrier dysfunction during inflammatory response to injury or infection. In this review, we provide a brief summary of the current knowledge on EV biology and advanced techniques in EV isolation and characterization. This is followed by a discussion focusing on the role and mechanisms of EVs in regulating blood-endothelium interactions and vascular permeability during inflammation. We conclude with a translational perspective on the diagnostic and therapeutic potential of EVs in vascular injury or infectious diseases, such as COVID-19.


Assuntos
Permeabilidade Capilar , Endotélio Vascular/metabolismo , Vesículas Extracelulares/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Endotélio Vascular/patologia , Endotélio Vascular/virologia , Vesículas Extracelulares/patologia , Vesículas Extracelulares/virologia , Interações Hospedeiro-Patógeno , Humanos , Inflamação/patologia , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Transdução de Sinais
10.
Phytomedicine ; 79: 153325, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920289

RESUMO

BACKGROUND: Panax notoginseng (Burk.) F.H. Chen is a traditional medicinal plant widely used to prevent and treat cardiovascular diseases. Ginsenoside Rd (GRd) is a major bioactive component of P. notoginseng, but specific effects on cardiovascular disease-related pathogenic processes are rarely studied, especially vascular endothelial injury. PURPOSE: This study investigated the potential protective efficacy of GRd against nicotine-induced vascular endothelial cell injury, disruption of vascular nitric oxide (NO) signaling, aberrant endothelium-monocyte adhesion, platelet aggregation, and vasoconstriction. STUDY DESIGN/METHODS: Vascular endothelial injury and functional disruption were investigated in cultured human umbilical vein endothelial cells (HUVECs) by biochemical assays for nitric oxide (NO) and angiotensin II (Ang II), immunofluorescence (IF) and western blotting for expression analyses of apoptosis- related proteins, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Ang II type receptor 1 (AGTR1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). In addition, vascular protection by GRd was examined in nicotine-administered Sprague-Dawley (SD) rats by serum NO and Ang II assays, and by hematoxylin-eosin (HE) and immunostaining of aorta. We also examined effects of GRd on monocyte (THP-1 cells) adhesion assays, adenosine diphosphate (ADP)-induced platelet aggregation, and phenylephrine (PE)-induced vasoconstriction of isolated rat aortic rings. RESULTS: In HUVECs, nicotine significantly suppressed NO production, enhanced Ang II production, downregulated eNOS expression, and upregulated expression levels of AGTR1, TLR4, MyD88, NF-κB, iNOS, Bax/Bcl-2 ratio, cleaved caspase-3, and cytochrome c (cyt c). All of these changes were significantly reversed by GRd. In rats, oral GRd reversed the reduction NO and enhanced Ang II production in serum induced by nicotine administration, and HE staining revealed protection of aortic endothelial cells. In addition, GRd reversed nicotine-mediated enhancement of HUVECs-monocyte adhesion, inhibited ADP-induced platelet aggregation and PE-induced vasoconstriction. CONCLUSION: GRd may prevent nicotine-induced cardiovascular diseases by preserving normal vascular endothelial NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing endothelial cell-monocyte adhesion.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Nicotina/toxicidade , Angiotensina II/sangue , Angiotensina II/metabolismo , Animais , Aorta/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ginsenosídeos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fenilefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor 4 Toll-Like/metabolismo , Triterpenos/química , Vasoconstrição/efeitos dos fármacos
11.
Toxicol Lett ; 333: 80-89, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738273

RESUMO

Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin-angiotensin system and COX2 pathway activation.


Assuntos
Cloreto de Cádmio/toxicidade , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hipertensão/induzido quimicamente , NADPH Oxidases/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Cloreto de Cádmio/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Poluentes Ambientais/sangue , Hipertensão/enzimologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Injeções Intraperitoneais , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos
12.
ACS Chem Neurosci ; 11(15): 2159-2162, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32786343

RESUMO

Immune system and renin-angiotensin-aldosterone system dysregulation with associated cytokine release syndrome may be a key feature of early stage of SARS-CoV-2 organotropism and infection. Following viral mediated brain injury, dysregulated neurochemical activity may cause neurogenic stress cardiomyopathy, which is characterized by transient myocardial dysfunction and arrhythmias. Cardiomyopathy along with acute acute inflammatory thromboembolism and endotheliitis (fragile endothelium) might at least partially explain the underlying mechanisms of rapidly evolving life-threatening COVID-19. Further studies are clearly required to explore these complex pathologies.


Assuntos
Betacoronavirus/metabolismo , Química Encefálica/fisiologia , Encéfalo/metabolismo , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Pneumonia Viral/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia
13.
Am J Physiol Heart Circ Physiol ; 319(4): H744-H752, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795193

RESUMO

Patients presenting with classical cardiovascular risk factors within acceptable or average value ranges often develop cardiovascular disease, suggesting that other risk factors need to be considered. Considering that endothelial progenitor cells (EPCs) contribute to endothelial repair, we investigated whether EPCs might be such a factor. We compared the ability of peripheral blood EPCs to attach to extracellular matrix proteins and to grow and function in culture, between controlled hypertensive patients exhibiting a Framingham score (FS) of <10% while showing severe vascular impairment (intima-media thickness/diameter, carotid-femoral pulse wave velocity, brachial artery flow-mediated dilation, carotid and femoral atherosclerotic plaque presence; vulnerable group, N = 30) and those with an FS of ≥10% and scarce vascular changes (protected group, N = 30). When compared with vulnerable patients, protected patients had significantly higher early and late-EPC and early and late-tunneling nanotube (TNT) numbers. Significant negative associations were found between vascular damage severity and early EPC, late-EPC, or late-TNT numbers, whereas EPC or TNT numbers and patient characteristics or cardiovascular risk factors were not associated. Except for protected patients, in all controlled hypertensive patients, early and late-EPC and early and late-TNT counts were significantly lower than those in the normotensive subjects studied (N = 30). We found that the disparity in vascular status between patients presenting with both an FS of ≥10% and scarce vascular changes and those presenting with both an FS of <10% and severe vascular impairment is related to differences in peripheral blood EPC and TNT numbers. These observations support the role of EPCs as contributors to vascular injury repair and suggest that EPC numbers may be a potential cardiovascular risk factor to be included in the FS calculation.NEW & NOTEWORTHY As individuals who present with risk factors within acceptable or average value ranges often develop cardiovascular (CV) disease, it has been suggested that other CV risk factors need to be considered in addition to those that are commonly combined in the Framingham score (FS) to estimate the risk of general CV disease. We investigated whether peripheral endothelial progenitor cells (EPCs) and tunneling nanotubes (TNTs) deserve to be considered. Here we report that EPCs and TNTs are significantly lower in controlled hypertensive patients versus normotensive subjects and that the disparity in vascular status between patients presenting with an FS of ≥10% with scarce vascular changes and those presenting with an FS of <10% with severe vascular impairment is related to differences in EPC and TNT numbers. These data point to EPC and TNT numbers as potential CV risk factors to be included in the FS calculation.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células , Células Progenitoras Endoteliais/patologia , Endotélio Vascular/patologia , Hipertensão/tratamento farmacológico , Regeneração , Adulto , Idoso , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Arterioscler Thromb Vasc Biol ; 40(10): 2404-2407, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32762443

RESUMO

OBJECTIVE: Alveolar-capillary endothelial cells can be activated by severe acute respiratory syndrome coronavirus 2 infection leading to cytokine release. This could trigger endothelial dysfunction, pyroptosis, and thrombosis, which are the vascular changes, commonly referred to as coronavirus disease 2019 (COVID-19) endotheliopathy. Thus, this study aimed to identify tissue biomarkers associated with endothelial activation/dysfunction and the pyroptosis pathway in the lung samples of patients with COVID-19 and to compare them to pandemic influenza A virus H1N1 subtype 2009 and control cases. Approach and Results: Postmortem lung samples (COVID-19 group =6 cases; H1N1 group =10 cases, and control group =11 cases) were analyzed using immunohistochemistry and the following monoclonal primary antibodies: anti-IL (interleukin)-6, anti-TNF (tumor necrosis factor)-α, anti-ICAM-1 (intercellular adhesion molecule 1), and anticaspase-1. From the result, IL-6, TNF-α, ICAM-1, and caspase-1 showed higher tissue expression in the COVID-19 group than in the H1N1 and control groups. CONCLUSIONS: Our results demonstrated endothelial dysfunction and suggested the participation of the pyroptosis pathway in the pulmonary samples. These conditions might lead to systemic thrombotic events that could impair the clinical staff's efforts to avoid fatal outcomes. One of the health professionals' goals should be to identify the high risk of thrombosis patients early to block endotheliopathy and its consequences.


Assuntos
Infecções por Coronavirus/patologia , Células Endoteliais/citologia , Endotélio Vascular/patologia , Pneumonia Viral/patologia , Trombose/patologia , Doenças Vasculares/patologia , Autopsia , Biópsia por Agulha , Causas de Morte , Infecções por Coronavirus/mortalidade , Células Endoteliais/patologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pandemias , Pneumonia Viral/mortalidade , Medição de Risco , Trombose/etiologia , Trombose/mortalidade , Doenças Vasculares/mortalidade , Doenças Vasculares/fisiopatologia
15.
Toxicol Lett ; 333: 97-104, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763312

RESUMO

Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Rim/efeitos dos fármacos , Pantoprazol/toxicidade , Inibidores da Bomba de Prótons/toxicidade , Administração Oral , Animais , Aorta Torácica/imunologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Rim/imunologia , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nitratos/metabolismo , Nitritos/metabolismo , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
16.
PLoS One ; 15(8): e0237141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764789

RESUMO

Severe dengue can be lethal caused by manifestations such as severe bleeding, fluid accumulation and organ impairment. This study aimed to investigate the role of dengue non-structural 1 (NS1) protein and host factors contributing to severe dengue. Electrical cell-substrate impedance sensing system was used to investigate the changes in barrier function of microvascular endothelial cells treated NS1 protein and serum samples from patients with different disease severity. Cytokines and metabolites profiles were assessed using a multiplex cytokine assay and liquid chromatography mass spectrometry respectively. The findings showed that NS1 was able to induce the loss of barrier function in microvascular endothelium in a dose dependent manner, however, the level of NS1 in serum samples did not correlate with the extent of vascular leakage induced. Further assessment of host factors revealed that cytokines such as CCL2, CCL5, CCL20 and CXCL1, as well as adhesion molecule ICAM-1, that are involved in leukocytes infiltration were expressed higher in dengue patients in comparison to healthy individuals. In addition, metabolomics study revealed the presence of deregulated metabolites involved in the phospholipid metabolism pathway in patients with severe manifestations. In conclusion, disease severity in dengue virus infection did not correlate directly with NS1 level, but instead with host factors that are involved in the regulation of junctional integrity and phospholipid metabolism. However, as the studied population was relatively small in this study, these exploratory findings should be confirmed by expanding the sample size using an independent cohort to further establish the significance of this study.


Assuntos
Citocinas/sangue , Vírus da Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Dengue Grave/sangue , Proteínas não Estruturais Virais/sangue , Linhagem Celular , Citocinas/imunologia , Citocinas/metabolismo , Vírus da Dengue/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Fosfolipídeos/metabolismo , Cultura Primária de Células , Dengue Grave/imunologia , Dengue Grave/metabolismo , Dengue Grave/patologia , Proteínas não Estruturais Virais/imunologia
17.
PLoS One ; 15(8): e0234492, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790760

RESUMO

Endothelial injury is a common manifestation in IgA nephropathy (IgAN). After the previous identification of the upregulated soluble fms-like tyrosine kinase-1 (sFlt-1) correlated with endothelial injury in IgAN, in the present study, we further explored the role of sFlt-1 in endothelial injury in IgAN. We enrolled 72 patients with IgAN and detected the sFlt-1 levels. The polymeric IgA1 (pIgA1) complexes were isolated from the pooled plasma samples of another 10 patients with IgAN. Apoptosis proteins were detected in cultured human umbilical vein endothelial cells (HUVECs) with the stimulation of recombinant sFlt-1 or the caspase-9 inhibitor Z-LEHD-FMK. We identified there were positive correlations between sFlt-1 and IgA-IgG complex as well as vWF levels in patients with IgAN. The sFlt-1 levels in HUVECs were significantly upregulated by pIgA1 complex derived from IgAN patients in a concentration-dependent manner. The proliferation ability of HUVECs was damaged when stimulated with sFlt-1 protein in a time- and dose- dependent manner. And the apoptosis rate was up-regulated significantly as the stimulation concentrations of sFlt-1 increased. We found sFlt-1 challenge could significantly increase the expression of vWF. In addition, sFlt-1 increased the levels of caspase-9, caspase-3, Bax and mitochondrial membrane potential; facilitated the release of cytochrome C from mitochondria to cytoplasma. In contrast, Z-LEHD-FMK attenuated high sFlt-1-induced HUVECs apoptosis. In conclusion, our study demonstrated that sFlt-1 expression was up-regulated by the challenge of pIgA1 complex derived from patients with IgAN. Furthermore, increased sFlt-1 facilitated human umbilical vein endothelial cells apoptosis via the mitochondrial-dependent pathway.


Assuntos
Endotélio Vascular/fisiopatologia , Glomerulonefrite por IGA/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Adulto , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Caspase 9/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Oligopeptídeos/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
18.
Metabolism ; 111: 154340, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32791171

RESUMO

BACKGROUND: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. PURPOSE: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. METHODS AND RESULTS: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. CONCLUSIONS: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.


Assuntos
Células Endoteliais/patologia , Endotélio Vascular/patologia , Obesidade/patologia , Estado Pré-Diabético/patologia , Animais , Sinalização do Cálcio/fisiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Obesidade/metabolismo , Estado Pré-Diabético/metabolismo , Ratos , Ratos Wistar , Vasodilatação/fisiologia
19.
EBioMedicine ; 58: 102925, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32745993

RESUMO

BACKGROUND: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.


Assuntos
Infecções por Coronavirus/patologia , Armadilhas Extracelulares/metabolismo , Microvasos/patologia , Neutrófilos/metabolismo , Pneumonia Viral/patologia , Trombose/metabolismo , Células Cultivadas , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Microvasos/metabolismo , Neutrófilos/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Trombose/etiologia , Trombose/patologia
20.
Biomolecules ; 10(8)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796765

RESUMO

Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a "treatment on a named-patient basis" approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0-16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/complicações , Endotélio Vascular/efeitos dos fármacos , Pneumonia Viral/complicações , Sepse/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Infecções por Coronavirus/patologia , Estado Terminal , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Sepse/etiologia
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