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1.
Int Heart J ; 61(5): 984-992, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921665

RESUMO

Uric acid is generated with reactive oxygen species via xanthine oxidase (XO), and hyperuricemia, which is identified as the excess of uric acid in the blood, has been associated with vascular endothelial dysfunction. However, the effects of urate-lowering medicines on endothelial function have not been fully elucidated. Thus this study determined and compared the effects of benzbromarone (urate transporter 1 inhibitor) and febuxostat (XO inhibitor) on endothelial function.This randomized, cross-over, open-label study initially recruited 30 patients with hyperuricemia. They were divided into two groups, treated initially with benzbromarone or febuxostat for three months and then were switched for the next three months. Endothelial function was defined as reactive hyperemia indexes (RHI) determined using Endo-PAT 2000 before and at three and six months after medication using the two agents. Blood levels of asymmetric dimethylarginine (ADMA) and high-molecular-weight (HMW) adiponectin were also compared. We finally analyzed data from 24 patients whose endothelial function was assessed as described above.Our findings show that levels of uric acid significantly decreased, whereas those of HMW adiponectin and the RHI have significantly increased after treatment with benzbromarone. Meanwhile, in patients administered with febuxostat, uric acid levels tended to decrease and RHI significantly decreased. Neither of the two agents altered ADMA levels. The changes in RHI (P = 0.026) and HMW adiponectin levels (P = 0.001) were found to be significantly greater in patients treated with benzbromarone than febuxostat. Changes in the levels of HMW adiponectin and of uric acid were significantly correlated (r = -0.424, P = 0.039).Benzbromarone has increased adiponectin besides reducing uric acid levels, and thus, this might confer more benefits on endothelial function than febuxostat.


Assuntos
Benzobromarona/uso terapêutico , Endotélio Vascular/fisiopatologia , Febuxostat/uso terapêutico , Hiperemia/fisiopatologia , Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Adiponectina/sangue , Idoso , Arginina/análogos & derivados , Arginina/sangue , Estudos Cross-Over , Feminino , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Resultado do Tratamento , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores
2.
Eur Heart J ; 41(32): 3038-3044, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882706

RESUMO

The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Endotélio Vascular/fisiopatologia , Estresse Oxidativo , Pneumonia Viral/complicações , Trombose/etiologia , Infecções por Coronavirus/epidemiologia , Citocinas/metabolismo , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Trombose/metabolismo , Trombose/fisiopatologia
3.
Trials ; 21(1): 746, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847626

RESUMO

OBJECTIVES: To investigate the effect of continuous infusion of the potential endothelial cytoprotective agent prostacyclin (Iloprost) 1 ng/kg/min vs. placebo for 72 hours on pulmonary endotheliopathy in mechanically ventilated COVID-19 patients. TRIAL DESIGN: A multicenter, randomized (1:1, active: placebo), blinded, parallel group exploratory trial PARTICIPANTS: Inclusion criteria are: Adult patients (>18 years); Confirmed COVID-19 infection; Need for mechanical interventions; Endothelial biomarker soluble thrombomodulin >4ng/ml. EXCLUSION CRITERIA: Withdrawal from active therapy; Pregnancy (non-pregnancy confirmed by patient being postmenopausal (age 60 or above) or having a negative urine- or plasma-hCG); Known hypersensitivity to iloprost or to any of the other ingredients; Previously included in this trial or a prostacyclin trial within 30 days; Consent cannot be obtained; Life-threatening bleeding defined by the treating physician; Known severe heart failure (NYHA class IV); Suspected acute coronary syndrome The study is conducted at five intensive care units in the Capital Region of Denmark at Rigshospitalet, Herlev Hospital, Hvidovre Hospital, Bispebjerg Hospital, Nordsjællands Hospital. INTERVENTION AND COMPARATOR: The patients are randomized to 72-hours continuous infusion of either prostacyclin (Iloprost/Ilomedin) at a dose of 1 ng/kg/min or Placebo (normal saline). MAIN OUTCOMES: Primary endpoint: Days alive without mechanical ventilation in the intensive care units within 28 days RANDOMISATION: The randomisation sequence is performed in permuted blocks of variable sizes stratified for trial site using centralised, concealed allocation. The randomisation sequence is generated 1:1 (active/placebo) using the online randomisation software 'Sealed Envelope' ( https://www.sealedenvelope.com/ ). Once generated the randomisation sequence is formatted and uploaded into Research Electronic Data Capture system (REDCap) to facilitate centralised, web-based allocation according to local written instruction. BLINDING (MASKING): The following are blinded: all clinicians, patients, investigators, and those assessing the outcomes including the statisticians. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Forty patients are planned to be randomized to each group, with a total sample size of 80 patients. TRIAL STATUS: Protocol version 1.4 dated May 25, 2020. Recruitment is ongoing. The recruitment was started June 15, 2020 and the anticipated finish of recruitment is February 28, 2021 with 90 days follow up hereafter. TRIAL REGISTRATION: Trial registration at clinicaltrialregisters.eu; EudraCT no. 2020-001296-33 on 3 April 2020 and at ClinicalTrials.gov Identifier: NCT04420741 on 9 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Infecções por Coronavirus/terapia , Iloprosta/uso terapêutico , Pneumonia Viral/terapia , Respiração Artificial , Vasodilatadores/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Dinamarca , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Pandemias , Pneumonia Viral/sangue , Trombomodulina/metabolismo
4.
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
5.
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
6.
High Blood Press Cardiovasc Prev ; 27(5): 363-371, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740853

RESUMO

Epigenetic processing takes centre stage in cardiometabolic diseases (obesity, metabolic syndrome, type 2 diabetes, hypertension), where it participates in adiposity, inflammation, endothelial dysfunction, vascular insulin resistance and atherosclerosis. Epigenetic modifications, defined as heritable changes in gene expression that do not entail mutation in the DNA sequence, are mainly induced by environmental stimuli (stress, pollution, cigarette smoking) and are gaining considerable interest due to their causal role in cardiovascular disease, and their amenability to pharmacological intervention. Importantly, epigenetic modifications acquired during life can be transmitted to the offspring and exert their biological effects across multiple generations. Indeed, such transgenerational transmission of epigenetic signals may contribute to anticipating cardiovascular and metabolic disease phenotypes already in children and young adults. A deeper understanding of environmental factors and their effects on the epigenetic machinery and transcriptional programs is warranted to develop effective mechanism-based therapeutic strategies. The clinical application of epigenetic drugs-also known as "epi-drugs"-is currently exploding in the field of cardiovascular disease. The present review describes the main epigenetic networks underlying cardiometabolic alterations and sheds light on specific points of intervention for pharmacological reprogramming in this setting.


Assuntos
Doenças Cardiovasculares/genética , Endotélio Vascular/metabolismo , Epigênese Genética , Síndrome Metabólica/genética , Animais , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Epigênese Genética/efeitos dos fármacos , Interação Gene-Ambiente , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Fatores de Risco , Transdução de Sinais
7.
Arterioscler Thromb Vasc Biol ; 40(9): 2293-2309, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757648

RESUMO

OBJECTIVE: Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P+, CD144+, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (P=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes (P<0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; P<0.05) and FGF (fibroblast growth factor; P<0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A. CONCLUSIONS: Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Vesículas Extracelulares/metabolismo , Neovascularização Fisiológica , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Idoso , Estudos de Casos e Controles , Células Cultivadas , Estudos Transversais , Células Endoteliais/ultraestrutura , Endotélio Vascular/fisiopatologia , Endotélio Vascular/ultraestrutura , Vesículas Extracelulares/ultraestrutura , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Selectina-P/metabolismo , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/ultraestrutura , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Clin Appl Thromb Hemost ; 26: 1076029620936350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649232
9.
Paediatr Respir Rev ; 35: 20-24, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653469

RESUMO

Since the initial description in 2019, the novel coronavirus SARS-Cov-2 infection (COVID-19) pandemic has swept the globe. The most severe form of the disease presents with fever and shortness of breath, which rapidly deteriorates to respiratory failure and acute lung injury (ALI). COVID-19 also presents with a severe coagulopathy with a high rate of venous thromboembiolism. In addition, autopsy studies have revealed co-localized thrombosis and inflammation, which is the signature of thromboinflammation, within the pulmonary capillary vasculature. While the majority of published data is on adult patients, there are parallels to pediatric patients. In our experience as a COVID-19 epicenter, children and young adults do develop both the coagulopathy and the ALI of COVID-19. This review will discuss COVID-19 ALI from a hematological perspective with discussion of the distinct aspects of coagulation that are apparent in COVID-19. Current and potential interventions targeting the multiple thromboinflammatory mechanisms will be discussed.


Assuntos
Lesão Pulmonar Aguda/sangue , Infecções por Coronavirus/sangue , Inflamação/sangue , Pneumonia Viral/sangue , Trombose/sangue , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/fisiopatologia , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Betacoronavirus , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/fisiopatologia , Capilares/imunologia , Capilares/fisiopatologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Inibidores do Fator Xa/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Pandemias , Ativação Plaquetária , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Embolia Pulmonar/fisiopatologia , Trombina/imunologia , Trombina/metabolismo , Trombose/tratamento farmacológico , Trombose/imunologia , Trombose/fisiopatologia
10.
Ther Adv Cardiovasc Dis ; 14: 1753944720934937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32611276

RESUMO

Ivabradine is a pure heart-rate lowering drug that is nowadays used, accordingly to the last ESC Guidelines, to reduce mortality and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction and in symptomatic patiens with inappropriate sinus tachycardia. Moreover, interesting effect of ivabradine on endothelial and myocardial function and on oxidative stress and inflamation pathways are progressively emerging. The aim of this paper is to highlight newer evidences about ivabradine effect (and consequently possible future application of the drug) in pathological settings different from guidelines-based clinical practice.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Ivabradina/uso terapêutico , Animais , Função Atrial/efeitos dos fármacos , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Ivabradina/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
11.
Arterioscler Thromb Vasc Biol ; 40(9): e240-e255, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698687

RESUMO

OBJECTIVE: To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K+) channels. Approach and Results: Endothelial dysfunction, observed as reduced dilations to flow, occurred after feeding mice a high-fat, Western diet for 8 weeks. The functional downregulation of endothelial Kir2.1 using dominant-negative Kir2.1 construct resulted in substantial reductions in the response to flow in mesenteric arteries of lean mice, whereas no effect was observed in arteries of obese mice. Overexpressing wild-type-Kir2.1 in endothelium of arteries from obese mice resulted in full recovery of the flow response. Exposing freshly isolated endothelial cells to fluid shear during patch-clamp electrophysiology revealed that the flow-sensitivity of Kir was virtually abolished in cells from obese mice. Atomic force microscopy revealed that the endothelial glycocalyx was stiffer and the thickness of the glycocalyx layer reduced in arteries from obese mice. We also identified that the length of the glycocalyx is critical to the flow-activation of Kir. Overexpressing Kir2.1 in endothelium of arteries from obese mice restored flow- and heparanase-sensitivity, indicating an important role for heparan sulfates in the flow-activation of Kir. Furthermore, the Kir2.1-dependent component of flow-induced vasodilation was lost in the endothelium of resistance arteries of obese humans obtained from biopsies collected during bariatric surgery. CONCLUSIONS: We conclude that obesity-induced impairment of flow-induced vasodilation is attributed to the loss of flow-sensitivity of endothelial Kir channels and propose that the latter is mediated by the biophysical alterations of the glycocalyx.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Glicocálix/metabolismo , Artérias Mesentéricas/metabolismo , Obesidade/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Vasodilatação , Adulto , Animais , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Feminino , Heparitina Sulfato/metabolismo , Humanos , Masculino , Mecanotransdução Celular , Potenciais da Membrana , Artérias Mesentéricas/fisiopatologia , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Fluxo Sanguíneo Regional
12.
Am J Physiol Heart Circ Physiol ; 319(2): H456-H467, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706261

RESUMO

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.


Assuntos
Antioxidantes/uso terapêutico , Artéria Braquial/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Claudicação Intermitente/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Artéria Poplítea/efeitos dos fármacos , Ubiquinona/análogos & derivados , Idoso , Antioxidantes/metabolismo , Pressão Arterial/efeitos dos fármacos , Artéria Braquial/metabolismo , Artéria Braquial/fisiopatologia , Estudos Cross-Over , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Contração Muscular/efeitos dos fármacos , Nebraska , Compostos Organofosforados/metabolismo , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/fisiopatologia , Artéria Poplítea/metabolismo , Artéria Poplítea/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Ubiquinona/metabolismo , Ubiquinona/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Caminhada
13.
Nat Commun ; 11(1): 3377, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632100

RESUMO

The mammary gland is a highly vascularized tissue capable of expansion and regression during development and disease. To enable mechanistic insight into the coordinated morphogenic crosstalk between the epithelium and vasculature, we introduce a 3D microfluidic platform that juxtaposes a human mammary duct in proximity to a perfused endothelial vessel. Both compartments recapitulate stable architectural features of native tissue and the ability to undergo distinct forms of branching morphogenesis. Modeling HER2/ERBB2 amplification or activating PIK3CA(H1047R) mutation each produces ductal changes observed in invasive progression, yet with striking morphogenic and behavioral differences. Interestingly, PI3KαH1047R ducts also elicit increased permeability and structural disorganization of the endothelium, and we identify the distinct secretion of IL-6 as the paracrine cause of PI3KαH1047R-associated vascular dysfunction. These results demonstrate the functionality of a model system that facilitates the dissection of 3D morphogenic behaviors and bidirectional signaling between mammary epithelium and endothelium during homeostasis and pathogenesis.


Assuntos
Glândulas Mamárias Humanas/metabolismo , Morfogênese/genética , Mutação , Comunicação Parácrina/genética , Biomimética/métodos , Linhagem Celular , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Glândulas Mamárias Humanas/irrigação sanguínea , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Fenótipo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
14.
Clin Rheumatol ; 39(9): 2529-2543, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32654082

RESUMO

The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy.


Assuntos
Infecções por Coronavirus/sangue , Endotélio Vascular/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Trombofilia/sangue , Trombose/sangue , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticoagulantes/uso terapêutico , Betacoronavirus/metabolismo , Plaquetas , Viscosidade Sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Endotélio Vascular/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio , Fibrinogênio/metabolismo , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Humanos , Pandemias , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativação Plaquetária , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Índice de Gravidade de Doença , Trombofilia/etiologia , Trombofilia/metabolismo , Trombose/tratamento farmacológico , Trombose/etiologia , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/uso terapêutico
15.
Life Sci ; 258: 118106, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682916

RESUMO

AIMS: Endothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. MAIN METHODS: The Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. KEY FINDINGS: Quercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SIGNIFICANCE: Quercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.


Assuntos
Autofagia/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Quercetina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
16.
Life Sci ; 258: 118124, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32702443

RESUMO

AIMS: Ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome. However, the effects of KD on hypertension have not been well investigated. The present study aimed to investigate the effects and underling mechanisms of KD on hypertension in spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS: SHRs were subjected to normal diet or KD for 4 weeks, starting at the age of 10 weeks. Then, the blood pressure and vascular function were assessed. Next, the eNOS expression, inflammatory factors and relative signaling pathway were examined. Human umbilical vein endothelial cells were used to investigate the underlying mechanism account for the effect of ketone on inflammation and eNOS expression. KEY FINDINGS: Compared with the normal diet, KD was indicated to aggravate hypertension and impaire endothelium-dependent relaxation in mesenteric arteries of SHRs. eNOS and CD31 expression in mesenteric arteries were also significantly suppressed by KD. In addition, KD markedly increased the activation of NF-κB pathway and the expression of IL1-ß and TNF-α. In vitro, results showed that inhibition of NF-κB could rescue the adverse effects of ketone body and TGF-ß on eNOS expression and inflammation response. SIGNIFICANCE: Our study indicated that KD impaired endothelium-dependent relaxation in mesenteric arteries and aggravated the development of hypertension in SHRs, suggesting that it should be more cautious to apply KD into clinical application in hypertensive individuals.


Assuntos
Dieta Cetogênica , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/metabolismo , Hipertensão/patologia , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Corpos Cetônicos/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Endogâmicos SHR , Vasodilatação , Perda de Peso
17.
Clin Appl Thromb Hemost ; 26: 1076029620936776, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687449

RESUMO

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Trombofilia/etiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticoagulantes/uso terapêutico , Arteriopatias Oclusivas/etiologia , Arteriopatias Oclusivas/fisiopatologia , Arteriopatias Oclusivas/virologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Cateterismo de Swan-Ganz , Terapia Combinada , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Endotélio Vascular/virologia , Fibrinolíticos/uso terapêutico , Humanos , Oxigenação Hiperbárica , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Embolia Pulmonar/etiologia , Embolia Pulmonar/terapia , Embolia Pulmonar/virologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Terapia Trombolítica/instrumentação , Terapia Trombolítica/métodos , Trombofilia/fisiopatologia , Trombofilia/terapia , Trombose Venosa/etiologia , Trombose Venosa/fisiopatologia , Trombose Venosa/virologia , Internalização do Vírus/efeitos dos fármacos
18.
Am J Physiol Heart Circ Physiol ; 319(2): H488-H506, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618516

RESUMO

Although chronic stress is an important risk factor for cardiovascular diseases (CVD) onset, the underlying mechanisms driving such pathophysiological complications remain relatively unknown. Here, dysregulation of innate stress response systems and the effects of downstream mediators are strongly implicated, with the vascular endothelium emerging as a primary target of excessive glucocorticoid and catecholamine action. Therefore, this review article explores the development of stress-related endothelial dysfunction by focusing on the following: 1) assessing the phenomenon of stress and complexities surrounding this notion, 2) discussing mechanistic links between chronic stress and endothelial dysfunction, and 3) evaluating the utility of various preclinical models currently employed to study mechanisms underlying the onset of stress-mediated complications such as endothelial dysfunction. The data reveal that preclinical models play an important role in our efforts to gain an increased understanding of mechanisms underlying stress-mediated endothelial dysfunction. It is our understanding that this provides a good foundation going forward, and we propose that further efforts should be made to 1) more clearly define the concept of stress and 2) standardize protocols of animal models with specific guidelines to better indicate the mental complications that are simulated.


Assuntos
Doenças Cardiovasculares/etiologia , Endotélio Vascular/fisiopatologia , Estresse Psicológico/complicações , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Catecolaminas/metabolismo , Doença Crônica , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Fatores de Risco , Transdução de Sinais , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia
19.
Arterioscler Thromb Vasc Biol ; 40(9): 2143-2158, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640903

RESUMO

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fertilidade/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Mutação Puntual , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Reepitelização/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
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