Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 15.638
Filtrar
1.
Nutrients ; 13(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34371945

RESUMO

Post-prandial hyperglycemia can be relevant in developing early manifestations of atherosclerosis. EVOO (Extra Virgin Olive Oil), rich in saturated fatty acids and commonly used in the Mediterranean diet, seems to control post-prandial hyperglycemia better than butter. Subjects with type 1 diabetes are at higher risk of developing cardiovascular disease and show endothelial dysfunction, an early manifestation of atherosclerosis in the first years of the disease. Our study aims to evaluate whether EVOO and butter influence endothelial function in subjects with type 1 diabetes when added to a single high glycemic index (HGI) meal. In this exploratory cross-over study, 10 subjects with type 1 diabetes and 6 healthy subjects were scheduled to receive two types of HGI meals: one enriched with EVOO and one with butter. Before and after each test meal at different time points, all subjects underwent the evaluation of endothelial function by flow-mediated dilation technique, glucose and lipids measurements, and gastric emptying assessment by ultrasound. Flow-mediated dilation significantly increased after EVOO-enriched meal compared with butter in subjects with type 1 diabetes (two-way-repeated measurements ANOVA, p = 0.007). In patients with type 1 diabetes, the add-on of EVOO to HGI meal improves vascular function compared to butter, which has detrimental effects.


Assuntos
Manteiga , Diabetes Mellitus Tipo 1/fisiopatologia , Gorduras na Dieta , Endotélio Vascular/fisiopatologia , Azeite de Oliva , Adulto , Velocidade do Fluxo Sanguíneo , Glicemia/análise , Pressão Sanguínea , Estudos Cross-Over , Feminino , Esvaziamento Gástrico , Índice Glicêmico , Humanos , Lipídeos/sangue , Masculino , Vasodilatação
2.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360549

RESUMO

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC4, PAF and VEGF can increase vascular permeability. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease.


Assuntos
Anafilaxia/patologia , Endotélio Vascular/fisiopatologia , Junções Comunicantes/patologia , Inflamação/fisiopatologia , Anafilaxia/etiologia , Anafilaxia/metabolismo , Animais , Permeabilidade Capilar , Humanos
3.
Arterioscler Thromb Vasc Biol ; 41(9): 2357-2369, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34196216

RESUMO

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane, and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, that is, a phenotypic modulation, that is sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating endothelial-to-mesenchymal transition have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increase permeability, which facilitates leukocyte trafficking, whereas endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete endothelial-to-mesenchymal transition proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In proadaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in maladaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how TGF (transforming growth factor) ß influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/patologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Transição Epitelial-Mesenquimal , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Movimento Celular , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Permeabilidade , Fenótipo , Transdução de Sinais
4.
BMC Neurol ; 21(1): 281, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281533

RESUMO

BACKGROUND: Previously published computational fluid dynamics (CFD) studies regarding intracranial aneurysm (IA) formation present conflicting results. Our study analysed the involvement of the combination of high wall shear stress (WSS) and a positive WSS gradient (WSSG) in IA formation. METHODS: We designed a case-control study with a selection of 38 patients with an unruptured middle cerebral artery (MCA) aneurysm and 39 non-aneurysmal controls to determine the involvement of WSS, oscillatory shear index (OSI), the WSSG and its absolute value (absWSSG) in aneurysm formation based on patient-specific CFD simulations using velocity profiles obtained from transcranial colour-coded sonography. RESULTS: Among the analysed parameters, only the WSSG had significantly higher values compared to the controls (11.05 vs - 14.76 [Pa/mm], P = 0.020). The WSS, absWSSG and OSI values were not significantly different between the analysed groups. Logistic regression analysis identified WSS and WSSG as significant co-predictors for MCA aneurysm formation, but only the WSSG turned out to be a significant independent prognosticator (OR: 1.009; 95% CI: 1.001-1.017; P = 0.025). Significantly more patients (23/38) in the case group had haemodynamic regions of high WSS combined with a positive WSSG near the bifurcation apex, while in the control group, high WSS was usually accompanied by a negative WSSG (14/39). From the analysis of the ROC curve for WSSG, the area under the curve (AUC) was 0.654, with the optimal cut-off value -0.37 Pa/mm. The largest AUC was recognised for combined WSS and WSSG (AUC = 0.671). Our data confirmed that aneurysms tend to form near the bifurcation apices in regions of high WSS values accompanied by positive WSSG. CONCLUSIONS: The development of IAs is determined by an independent effect of haemodynamic factors. High WSS impacts MCA aneurysm formation, while a positive WSSG mainly promotes this process.


Assuntos
Simulação por Computador , Endotélio Vascular/fisiopatologia , Aneurisma Intracraniano/fisiopatologia , Modelos Cardiovasculares , Estresse Mecânico , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Estudos de Casos e Controles , Endotélio Vascular/diagnóstico por imagem , Feminino , Hemodinâmica , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler Transcraniana , Adulto Jovem
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201520

RESUMO

Autophagy is a vital cell mechanism which plays an important role in many physiological processes including clearing long-lived, accumulated and misfolded proteins, removing damaged organelles and regulating growth and aging. Autophagy also participates in a variety of biological functions, such as development, cell differentiation, resistance to pathogens and nutritional hunger. Recently, autophagy has been reported to be involved in diabetes, but the mechanism is not fully understood. Hydrogen sulfide (H2S) is a colorless, water-soluble, flammable gas with the typical odor of rotten eggs, which has been known as a highly toxic gas for many years. However, it has been reported recently that H2S, together with nitric oxide and carbon monoxide, is an important gas signal transduction molecule. H2S has been reported to play a protective role in many diabetes-related diseases, but the mechanism is not fully clear. Recent studies indicate that H2S plays an important role by regulating autophagy in many diseases including cancer, tissue fibrosis diseases and glycometabolic diseases; however, the related mechanism has not been fully studied. In this review, we summarize recent research on the role of H2S in regulating autophagy in diabetic-related diseases to provide references for future related research.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus/fisiopatologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Animais , Autofagia/fisiologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Diabetes Mellitus/psicologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Humanos , Sulfeto de Hidrogênio/farmacocinética , Transdução de Sinais
6.
Int J Lab Hematol ; 43 Suppl 1: 29-35, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34288441

RESUMO

Vascular endothelial injury is a hallmark of acute infection at both the microvascular and macrovascular levels. The hallmark of SARS-CoV-2 infection is the current COVID-19 clinical sequelae of the pathophysiologic responses of hypercoagulability and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID-19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID-19-associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflammatory injury we see clinically in critically ill patients.


Assuntos
COVID-19/complicações , Pandemias , SARS-CoV-2 , Trombofilia/etiologia , Vasculite/etiologia , Anticoagulantes/uso terapêutico , COVID-19/sangue , COVID-19/imunologia , Criança , Coagulação Intravascular Disseminada/etiologia , Endotélio Vascular/lesões , Endotélio Vascular/fisiopatologia , Feminino , Fibrinólise , Previsões , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Tromboembolia/etiologia , Tromboembolia/prevenção & controle
8.
Respir Med ; 185: 106469, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34175806

RESUMO

BACKGROUND: The prothrombotic phenotype and diffuse intravascular coagulation observed in COVID-19 reflect endothelial dysfunction, which is linked to blood flow delivery deficiencies and cardiovascular risk. Assessments of detect vascular deficiencies among newly diagnosed and hospitalized patients due to COVID-19 have yet to be determined. OBJECTIVE: To assess endothelial function characteristics in relation to length of hospitalization and mortality in patients diagnosed with COVID-19 and compare to patients without COVID-19. METHODS: A prospective observational study involving 180 patients with confirmed COVID-19 (COVID-19 group) or suspected and ruled out COVID-19 (Non-COVID-19 group). Clinical evaluation and flow mediated vasodilation (FMD) were performed between the first 24-48 h of hospitalization. Patients were followed until death or discharge. RESULTS: We evaluated 98 patients (COVID-19 group) and 82 (Non-COVID-19 group), COVID-19 group remained hospitalized longer and more deaths occurred compared to the Non-COVID-19 group (p = 0.01; and p < 0.01). Patients in COVID-19 group also had a significantly greater reduction in both FMDmm and FMD% (p < 0.01 in both). We found that absolute FMD≤0.26 mm and relative FMD≤3.43% were the ideal cutoff point to predict mortality and longer hospital stay. In Kaplan Meyer's analysis patients had a high probability of death within a period of up to 10 days of hospitalization. CONCLUSION: Patients hospitalized for COVID-19 present endothelial vascular dysfunction early, remained hospitalized longer and had a higher number of deaths, when compared with patients without COVID-19.


Assuntos
Artéria Braquial/fisiopatologia , COVID-19/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia , Doenças Cardiovasculares/epidemiologia , Comorbidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2 , Estados Unidos/epidemiologia
9.
Expert Opin Ther Targets ; 25(6): 423-433, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34167431

RESUMO

INTRODUCTION: Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. AREAS COVERED: We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. EXPERT OPINION: Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.


Assuntos
COVID-19/complicações , Endotélio Vascular/efeitos dos fármacos , Polidesoxirribonucleotídeos/farmacologia , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/etiologia , COVID-19/fisiopatologia , COVID-19/virologia , Endotélio Vascular/fisiopatologia , Humanos , Polidesoxirribonucleotídeos/uso terapêutico , SARS-CoV-2/isolamento & purificação
10.
Thorax ; 76(6): 618-620, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34157671

RESUMO

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.


Assuntos
Endotélio Vascular/fisiopatologia , Temperatura Alta , Estresse Oxidativo , Ativação Plaquetária/fisiologia , Fumar/metabolismo , Produtos do Tabaco/estatística & dados numéricos , Vaping , Idoso , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/fisiopatologia
11.
PLoS One ; 16(6): e0253347, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34161337

RESUMO

The unprecedented global COVID-19 pandemic has prompted a desperate international effort to accelerate the development of anti-viral candidates. For unknown reasons, COVID-19 infections are associated with adverse cardiovascular complications, implicating that vascular endothelial cells are essential in viral propagation. The etiological pathogen, SARS-CoV-2, has a higher reproductive number and infection rate than its predecessors, indicating it possesses novel characteristics that infers enhanced transmissibility. A unique K403R spike protein substitution encodes an Arg-Gly-Asp (RGD) motif, introducing a potential role for RGD-binding host integrins. Integrin αVß3 is widely expressed across the host, particularly in the endothelium, which acts as the final barrier before microbial entry into the bloodstream. This mutagenesis creates an additional binding site, which may be sufficient to increase SARS-CoV-2 pathogenicity. Here, we investigate how SARS-CoV-2 passes from the epithelium to endothelium, the effects of αVß3 antagonist, Cilengitide, on viral adhesion, vasculature permeability and leakage, and also report on a simulated interaction between the viral and host protein in-silico.


Assuntos
Endotélio Vascular/virologia , Integrina alfaVbeta3/metabolismo , SARS-CoV-2/patogenicidade , Venenos de Serpentes/farmacologia , Antígenos CD/metabolismo , Sítios de Ligação , COVID-19/metabolismo , COVID-19/fisiopatologia , Células CACO-2 , Caderinas/metabolismo , Simulação por Computador , Endotélio Vascular/citologia , Endotélio Vascular/fisiopatologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Integrina alfaVbeta3/química , Modelos Moleculares , Mutação , Permeabilidade , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
12.
Isr Med Assoc J ; 23(6): 364-368, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34155850

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common clinical entity, with a mechanism that appears to involve endothelial dysfunction of the cardiac microcirculation. Endothelial progenitor cells (EPC) are bone marrow derived cells that are able to differentiate into functional endothelial cells and participate in endothelial surface repair. OBJECTIVES: To compare the level and function of EPCs in patients with HFpEF compared with heart failure with reduced ejection fraction (HFrEF) and control subjects. METHODS: We enrolled 21 patients with HFpEF (LVEF ≥ 50%, age 74.5 ± 9.9 years, 43% men, 48% diabetes), 20 patients with HFrEF (LVEF < 40%, age 70 ± 11.5 years, 90% men, 60% diabetes), and 11 control subjects with cardiovascular risk factors (age 53.3 ± 6.1years, 90% men, 64% diabetes). Circulating EPC levels were evaluated by expression of vascular endothelial growth factor receptor-2 (VEGFR-2), CD34, and CD133 by flow-cytometry. EPCs colony forming units (CFUs) were quantified after 7 days in culture. RESULTS: The proportion of cells that co-expressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was similar among the HFpEF and HFrEF groups, and significantly lower than in the control group. The number of EPC-CFUs was also similar among the two heart failure groups and significantly lower than the control group. CONCLUSIONS: Patients with HFpEF, like HFrEF, have significant reduction in EPC level and function.


Assuntos
Antígeno AC133/sangue , Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular , Insuficiência Cardíaca , Volume Sistólico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Idoso , Ensaio de Unidades Formadoras de Colônias/métodos , Circulação Coronária , Correlação de Dados , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade
13.
Pharmacol Rev ; 73(3): 924-967, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34088867

RESUMO

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1ß monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.


Assuntos
Aterosclerose , COVID-19 , Fármacos Cardiovasculares , Doenças Cardiovasculares , Endotélio Vascular , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/fisiopatologia , Fármacos Cardiovasculares/classificação , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Descoberta de Drogas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , SARS-CoV-2
14.
Am J Physiol Heart Circ Physiol ; 321(1): H1-H14, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33989084

RESUMO

We tested the hypothesis that adiponectin deficiency attenuates cardiac and coronary microvascular function and prevents exercise training-induced adaptations of the myocardium and the coronary microvasculature in adult mice. Adult wild-type (WT) or adiponectin knockout (adiponectin KO) mice underwent treadmill exercise training or remained sedentary for 8-10 wk. Systolic and diastolic functions were assessed before and after exercise training or cage confinement. Vasoreactivity of coronary resistance arteries was assessed at the end of exercise training or cage confinement. Before exercise training, ejection fraction and fractional shortening were similar in adiponectin KO and WT mice, but isovolumic contraction time was significantly lengthened in adiponectin KO mice. Exercise training increased ejection fraction (12%) and fractional shortening (20%) with no change in isovolumic contraction time in WT mice. In adiponectin KO mice, both ejection fraction (-9%) and fractional shortening (-12%) were reduced after exercise training and these decreases were coupled to a further increase in isovolumic contraction time (20%). In sedentary mice, endothelium-dependent dilation to flow was higher in arterioles from adiponectin KO mice as compared with WT mice. Exercise training enhanced dilation to flow in WT mice but decreased flow-induced dilation in adiponectin KO mice. These data suggest that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice lacking adiponectin; however, in the absence of adiponectin, cardiac and coronary microvascular adaptations to exercise training are compromised.NEW & NOTEWORTHY We report that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice in which adiponectin has been deleted; however, when mice lacking adiponectin are subjected to the physiological stress of exercise training, beneficial coronary microvascular and cardiac adaptations are compromised or absent.


Assuntos
Adiponectina/genética , Coração/fisiologia , Condicionamento Físico Animal/fisiologia , Vasodilatação/fisiologia , Adiponectina/metabolismo , Animais , Endotélio Vascular/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Microvasos/fisiologia , Miocárdio/metabolismo
15.
Am J Physiol Heart Circ Physiol ; 321(1): H29-H37, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34018853

RESUMO

Black Americans have an earlier onset, higher average blood pressure, and higher rates of hypertension-related mortality and morbidity, compared to whites. The racial difference may be related to microvasculature, the major regulatory site of blood pressure. The goal of this study was to compare the response of resistance vessels to high intraluminal pressure between black and white participants. A total of 38 vessels were obtained from human fat samples [21 black, 17 white; mean age 32 ± 12 yr and body mass index (BMI) 26.9 ± 4.9; between-group P ≥ 0.05] and included in this study. Internal diameter was measured in response to the flow induced by various pressure gradients (Δ10, Δ20, Δ40, Δ60, and Δ100 cmH2O), and flow-induced dilation (FID) was calculated before and after high intraluminal pressure (150 cmH2O). Before high intraluminal pressure, FID was not different between blacks and whites (P = 0.112). After exposure to high intraluminal pressure, FID was reduced at every pressure gradient in vessels from blacks (P < 0.001), whereas FID did not change in white participants except at Δ100 cmH2O. When incubated with the hydrogen peroxide (H2O2) scavenger polyethylene glycol-catalase (PEG-catalase), the FID response in vessels from black, but not white, individuals was significantly reduced and the magnitude was higher at normal pressure relative to high pressure. Our findings suggest that the vessels from self-identified black individuals are more susceptible to microvascular dysfunction following transient periods of high intraluminal pressure compared to whites and show greater dependence on H2O2 as a main contributor to FID at normal pressures.NEW & NOTEWORTHY Microvascular function regulates blood pressure and may contribute to racial differences in the incidence and prevalence of hypertension and other cardiovascular diseases. Here, we show that using an ex vivo model of resistance arterioles isolated from human gluteal fat tissue, flow-induced dilation is not different between black and white participants. However, when exposed to transient increases in intraluminal pressure, the flow-induced dilation in resistance arterioles from black participants demonstrated greater reductions relative to their white counterparts, indicating a higher sensitivity to pressure change in the microvasculature.


Assuntos
Arteríolas/fisiopatologia , Pressão Sanguínea/fisiologia , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Adulto , Afro-Americanos , Velocidade do Fluxo Sanguíneo/fisiologia , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Adulto Jovem
16.
PLoS One ; 16(5): e0252026, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34038475

RESUMO

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.


Assuntos
COVID-19/patologia , Citocinas/metabolismo , Fígado/fisiopatologia , Pulmão/fisiopatologia , Obesidade/patologia , Idoso , Biomarcadores/metabolismo , Índice de Massa Corporal , COVID-19/complicações , COVID-19/virologia , Quimiocinas/sangue , Quimiocinas/metabolismo , Citocinas/sangue , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva , Fígado/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Prospectivos , RNA Viral/sangue , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
17.
Respir Res ; 22(1): 148, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985491

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been linked to thrombotic complications and endothelial dysfunction. We assessed the prognostic implications of endothelial activation through measurement of endothelin-I precursor peptide (proET-1), the stable precursor protein of Endothelin-1, in a well-defined cohort of patients hospitalized with COVID-19. METHODS: We measured proET-1 in 74 consecutively admitted adult patients with confirmed COVID-19 and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and viral bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality. RESULTS: Overall, median admission proET-1 levels were lower in COVID-19 patients compared to those with pneumonia and exacerbated bronchitis, respectively (57.0 pmol/l vs. 113.0 pmol/l vs. 96.0 pmol/l, p < 0.01). Although COVID-19 non-survivors had 1.5-fold higher admission proET-1 levels compared to survivors (81.8 pmol/l [IQR: 76 to 118] vs. 53.6 [IQR: 37 to 69]), no significant association of proET-1 levels and mortality was found in a regression model adjusted for age, gender, creatinine level, diastolic blood pressure as well as cancer and coronary artery disease (adjusted OR 0.1, 95% CI 0.0009 to 14.7). In patients with pneumonia (adjusted OR 25.4, 95% CI 5.1 to 127.4) and exacerbated bronchitis (adjusted OR 120.1, 95% CI 1.9 to 7499) we found significant associations of proET-1 and mortality. CONCLUSIONS: Compared to other types of pulmonary infection, COVID-19 shows only a mild activation of the endothelium as assessed through measurement of proET-1. Therefore, the high mortality associated with COVID-19 may not be attributed to endothelial dysfunction by the surrogate marker proET-1.


Assuntos
COVID-19/mortalidade , COVID-19/fisiopatologia , Endotelina-1/análise , Endotélio Vascular/fisiopatologia , Precursores de Proteínas/análise , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Pressão Sanguínea , Estudos de Coortes , Creatinina/sangue , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Fatores Sexuais , Análise de Sobrevida
18.
Biomolecules ; 11(3)2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799818

RESUMO

(1) Background: Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Myocardial oxygenation and perfusion response to stress, using oxygen-sensitive cardiovascular magnetic resonance (OS-CMR) and stress T1 mapping respectively, are impaired in CKD patients with and without known coronary artery disease (CAD). Endothelial dysfunction, assessed by circulating levels of asymmetric dimethylarginine (ADMA) and homoarginine (HMA), promotes atherosclerosis. We hypothesized that in CKD patients, worsening endothelial dysfunction is associated with worsening myocardial oxygenation and perfusion as assessed by change in OS-CMR signal intensity (Δ OS-CMR SI) and stress T1 (ΔT1) values. (2) Methods: 38 patients with advanced CKD underwent cardiovascular magnetic resonance (CMR) scanning at 3 Tesla. OS-CMR and T1 mapping images were acquired both at rest and after adenosine stress and analyzed semi-quantitatively. Serum ADMA and HMA concentrations were assessed using mass spectrometry. (3) Results: There was no significant correlation between Δ OS-CMR SI and ADMA or HMA. Interestingly, there was a significant negative correlation seen between Δ T1 and ADMA (r = -0.419, p = 0.037, n = 30) but not between Δ T1 and HMA. (4) Conclusions: Stress T1 response is impaired in CKD patients and is independently associated with higher circulating ADMA concentrations.


Assuntos
Arginina/metabolismo , Imageamento por Ressonância Magnética , Metaboloma , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/metabolismo , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/metabolismo , Biomarcadores/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus/metabolismo , Diálise , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/fisiopatologia , Tamanho do Órgão , Oxigênio , Volume Sistólico , Troponina T/metabolismo
19.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33836561

RESUMO

Interferonopathies, interferon (IFN)-α/ß therapy, and caveolin-1 (CAV1) loss-of-function have all been associated with pulmonary arterial hypertension (PAH). Here, CAV1-silenced primary human pulmonary artery endothelial cells (PAECs) were proliferative and hypermigratory, with reduced cytoskeletal stress fibers. Signal transducers and activators of transcription (STAT) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) were both constitutively activated in these cells, resulting in a type I IFN-biased inflammatory signature. Cav1 -/- mice that spontaneously develop pulmonary hypertension were found to have STAT1 and AKT activation in lung homogenates and increased circulating levels of CXCL10, a hallmark of IFN-mediated inflammation. PAH patients with CAV1 mutations also had elevated serum CXCL10 levels and their fibroblasts mirrored phenotypic and molecular features of CAV1-deficient PAECs. Moreover, immunofluorescence staining revealed endothelial CAV1 loss and STAT1 activation in the pulmonary arterioles of patients with idiopathic PAH, suggesting that this paradigm might not be limited to rare CAV1 frameshift mutations. While blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways simultaneously. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling and NOS3 dysregulation in the inflammatory phenotype. Exogenous IFN reduced CAV1 expression, activated STAT1 and AKT, and altered the cytoskeleton of PAECs, implicating these mechanisms in PAH associated with autoimmune and autoinflammatory diseases, as well as IFN therapy. CAV1 insufficiency elicits an IFN inflammatory response that results in a dysfunctional endothelial cell phenotype and targeting this pathway may reduce pathologic vascular remodeling in PAH.


Assuntos
Caveolina 1/genética , Endotélio Vascular/metabolismo , Hipertensão Pulmonar/metabolismo , Interferon Tipo I/metabolismo , Animais , Células Cultivadas , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Inativação Gênica , Humanos , Hipertensão Pulmonar/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...