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1.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299162

RESUMO

IgA, previously called Henoch-Schönlein vasculitis, is an essential immune component that drives the host immune response to the external environment. As IgA has the unique characteristic of a flexible response to broad types of microorganisms, it sometimes causes an autoreactive response in the host human body. IgA vasculitis and related organ dysfunction are representative IgA-mediated autoimmune diseases; bacterial and viral infections often trigger IgA vasculitis. Recent drug developments and the presence of COVID-19 have revealed that these agents can also trigger IgA vasculitis. These findings provide a novel understanding of the pathogenesis of IgA vasculitis. In this review, we focus on the characteristics of IgA and symptoms of IgA vasculitis and other organ dysfunction. We also mention the therapeutic approach, biomarkers, novel triggers for IgA vasculitis, and epigenetic modifications in patients with IgA vasculitis.


Assuntos
Biomarcadores/análise , Epigênese Genética , Imunoglobulina A/metabolismo , Vasculite/terapia , Animais , Humanos , Vasculite/diagnóstico , Vasculite/etiologia , Vasculite/metabolismo
2.
Front Immunol ; 12: 663412, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079548

RESUMO

Endothelial inflammation and damage are the main drivers of cardiovascular risk/disease. Endothelial repair is mediated in part by recruitment of bone marrow endothelial progenitor/endothelial colony forming cells (EPC/ECFC). People with HIV (PWH) have increased cardiovascular risk and the impact of infection in endothelial repair is not well defined. The low frequencies and challenges to in vitro isolation and differentiation of EPC/ECFC from PBMCs had made it difficult to study their role in this context. We hypothesized that HIV driven inflammation induces phenotypic changes that reflects the impact of infection. To test this hypothesis, we evaluated expression of markers of trafficking, endothelial differentiation, and angiogenesis, and study their association with biomarkers of inflammation in a cohort of PWH. In addition, we investigated the relationship of circulating endothelial progenitors and angiogenic T cells, a T cell subset with angiogenic function. Using a flow cytometry approach, we identified two subsets of circulating progenitors LIN4-CD45-CD34+ and LIN4-CD45dimCD34+ in PWH. We found that the phenotype but not frequencies were associated with biomarkers of inflammation. In addition, the percentage of LIN4-CD45dimCD34+ was associated with serum levels of lipids. This data may provide a new tool to better address the impact of HIV infection in endothelial inflammation and repair.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Infecções por HIV/complicações , Infecções por HIV/imunologia , Vasculite/etiologia , Vasculite/metabolismo , Idoso , Biomarcadores , Relação CD4-CD8 , Doença Crônica , Células Progenitoras Endoteliais/patologia , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Imunofenotipagem , Mediadores da Inflamação , Metabolismo dos Lipídeos , Lipídeos/sangue , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vasculite/patologia
3.
Front Immunol ; 12: 640315, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079539

RESUMO

Innate immune activity plays an essential role in the development of Kawasaki disease (KD) vasculitis. Extracellular release of high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular pattern protein that can activate the innate immune system and drive host inflammatory responses, may contribute to the development of coronary artery abnormalities in KD. Prednisolone (PSL) added to intravenous immunoglobulin treatment for acute KD may reduce such abnormalities. Here, we evaluate the dynamics of HMGB-1 and therapeutic effects of PSL on HMGB-1-mediated inflammatory pathways on KD vasculitis in vitro. Serum samples were collected prior to initial treatment from patients with KD, systemic juvenile idiopathic arthritis (sJIA), and from healthy controls (VH), then incubated with human coronary artery endothelial cells (HCAECs). Following treatment of KD serum-activated HCAECs with PSL or PBS as a control, effects on the HMGB-1 signaling pathway were evaluated. Compared to that from VH and sJIA, KD serum activation induced HCAEC cytotoxicity and triggered extracellular release of HMGB-1. KD serum-activated HCAECs up-regulated extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and, p38 phosphorylation in the cytoplasm and nuclear factor kappa B (NF-κB) phosphorylation in the nucleus and increased interleukin (IL)-1ß and tumor necrosis factor (TNF)-α production. PSL treatment of KD serum-activated HCAECs inhibited extracellular release of HMGB-1, down-regulated ERK1/2, JNK, p38, and NF-κB signaling pathways, and decreased IL-1ß and TNF-α production. Our findings suggest that extracellular HMGB-1 plays an important role in mediating KD pathogenesis and that PSL treatment during the acute phase of KD may ameliorate HMGB-1-mediated inflammatory responses in KD vasculitis.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína HMGB1/metabolismo , Síndrome de Linfonodos Mucocutâneos/metabolismo , Prednisolona/farmacologia , Células Cultivadas , Vasos Coronários , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Proteína HMGB1/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Vasculite/etiologia , Vasculite/metabolismo
4.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917744

RESUMO

Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events in the development and pathophysiology of atherosclerosis and are associated with an elevated risk of cardiovascular events. There is great interest to further understand the pathophysiologic mechanisms underlying endothelial dysfunction and atherosclerosis progression, and to identify novel biomarkers and therapeutic strategies to prevent endothelial dysfunction, atherosclerosis and to reduce the risk of developing CAD and its complications. The use of liquid biopsies and new molecular biology techniques have allowed the identification of a growing list of molecular and cellular markers of endothelial dysfunction, which have provided insight on the molecular basis of atherosclerosis and are potential biomarkers and therapeutic targets for the prevention and or treatment of atherosclerosis and CAD. This review describes recent information on normal vascular endothelium function, as well as traditional and novel potential biomarkers of endothelial dysfunction and inflammation, and pharmacological and non-pharmacological therapeutic strategies aimed to protect the endothelium or reverse endothelial damage, as a preventive treatment for CAD and related complications.


Assuntos
Biomarcadores , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Vasculite/etiologia , Vasculite/metabolismo , Animais , Permeabilidade Capilar , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/fisiopatologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Hemostasia , Humanos , Terapia de Alvo Molecular/métodos , Vasculite/tratamento farmacológico , Vasculite/fisiopatologia
5.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495831

RESUMO

Chronic vascular inflammatory response is an important pathological basis of cardiovascular disease. Genistein (GEN), a natural compound, exhibits anti­inflammatory effects. The aim of the present study was to investigate the effects of GEN on lipopolysaccharide (LPS)­induced chronic vascular inflammatory response in mice and explore the underlying anti­inflammatory mechanisms. C57BL/6 mice were fed with a high­fat diet combined with intraperitoneal injection of LPS to induce chronic vascular inflammation. The expression levels of TNF­α, IL­6 and microRNA (miR)­21 in the vasculature were detected via reverse transcription­quantitative (RT­q)PCR. The protein levels of inducible nitric oxide synthase (iNOS) and NF­κB p65 were detected via western blotting. NF­κB p65 was also analyzed via immunohistochemistry and immunofluorescence (IF). In addition, after transfection with miR­21 mimic or inhibitor for 24 h, vascular endothelial cells (VECs) were treated with GEN and LPS. RT­qPCR and western blot analyses were performed to detect the expression of TNF­α, IL­6, miR­21 and iNOS, and the protein levels of iNOS and NF­κB p65, respectively. IF was used to measure NF­κB p65 nuclear translocation. The results revealed that GEN significantly decreased the expression of inflammation­associated vascular factors in LPS­treated C57BL/6 mice, including TNF­α, IL­6, iNOS, NF­κB p65 and miR­21. Furthermore, miR­21 antagomir enhanced the anti­inflammatory effects of GEN. In LPS­induced VECs, miR­21 mimic increased inflammation­associated factor expression and attenuated the anti­inflammatory effects of GEN, whereas miR­21 inhibitor induced opposing effects. Therefore, the results of the present study suggested that GEN inhibited chronic vascular inflammatory response in mice, which may be associated with the inhibition of VEC inflammatory injury via the miR­21/NF­κB p65 pathway.


Assuntos
Células Endoteliais/metabolismo , Genisteína/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , MicroRNAs/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Vasculite/metabolismo , Animais , Doença Crônica , Células Endoteliais/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Masculino , Camundongos , MicroRNAs/genética , Fator de Transcrição RelA/genética , Vasculite/induzido quimicamente , Vasculite/tratamento farmacológico , Vasculite/genética
6.
FASEB J ; 35(1): e21133, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33184917

RESUMO

Chronic vascular inflammation plays a key role in the pathogenesis of atherosclerosis. Long non-coding RNAs (lncRNAs) have emerged as essential inflammation regulators. We identify a novel lncRNA termed lncRNA-MAP3K4 that is enriched in the vessel wall and regulates vascular inflammation. In the aortic intima, lncRNA-MAP3K4 expression was reduced by 50% during the progression of atherosclerosis (chronic inflammation) and 70% during endotoxemia (acute inflammation). lncRNA-MAP3K4 knockdown reduced the expression of key inflammatory factors (eg, ICAM-1, E-selectin, MCP-1) in endothelial cells or vascular smooth muscle cells and decreased monocytes adhesion to endothelium, as well as reducing TNF-α, IL-1ß, COX2 expression in macrophages. Mechanistically, lncRNA-MAP3K4 regulates inflammation through the p38 MAPK signaling pathway. lncRNA-MAP3K4 shares a bidirectional promoter with MAP3K4, an upstream regulator of the MAPK signaling pathway, and regulates its transcription in cis. lncRNA-MAP3K4 and MAP3K4 show coordinated expression in response to inflammation in vivo and in vitro. Similar to lncRNA-MAP3K4, MAP3K4 knockdown reduced the expression of inflammatory factors in several different vascular cells. Furthermore, lncRNA-MAP3K4 and MAP3K4 knockdown showed cooperativity in reducing inflammation in endothelial cells. Collectively, these findings unveil the role of a novel lncRNA in vascular inflammation by cis-regulating MAP3K4 via a p38 MAPK pathway.


Assuntos
Regulação da Expressão Gênica , MAP Quinase Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/metabolismo , Vasculite/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , MAP Quinase Quinase Quinase 4/genética , Camundongos , RNA Longo não Codificante/genética , Vasculite/genética , Vasculite/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
7.
J Clin Invest ; 131(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32990682

RESUMO

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.


Assuntos
Envelhecimento/metabolismo , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Endotélio Vascular/metabolismo , Receptores de Complemento/metabolismo , Vasculite/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Barreira Hematoencefálica/patologia , Complemento C3a/genética , Complemento C3a/metabolismo , Endotélio Vascular/patologia , Camundongos , Camundongos Knockout , Receptores de Complemento/genética , Vasculite/genética , Vasculite/patologia
8.
J Mol Neurosci ; 71(2): 225-233, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32748330

RESUMO

The proliferation and migration of vascular smooth muscle cells (VSMCs) are involved in the pathogenesis of intracranial aneurysm (IA) formation and rupture. Interleukin enhancer binding factor 2 (ILF2) is known as the nuclear factor of activated T cells and regulates cell growth. This study was aimed to explore the effects of ILF2 on IA progression. Human brain VSMCs (hBVSMCs) were transfected with pCDNA3.1(+), pCDNA3.1(+)-ILF2, siRNA-negative control, and siRNA-ILF2. The transfection efficiency was then evaluated by determining ILF2 expression. The cell viability and apoptosis were determined using Cell Counting Kit-8 and Annexin V-FITC cell apoptosis assay kit, respectively. Real-time quantification PCR (RT-qPCR) was applied to measure the expression levels of apoptosis-related and inflammation-related genes. Finally, western blot was used to detect the expression level of Fas cell surface death receptor 95 (CD95) and Caspase 8. Overexpression of ILF2 could significantly increase cell viability and decrease cell apoptosis (P < 0.05), while knock-down of ILF2 showed opposite trends for hBVSMCs on cell viability and apoptosis (P < 0.05). RT-qPCR results showed that ILF2 knock-down downregulated the expression levels of BCL2 apoptosis regulator (BCL2), transcriptional regulator Myc-like (c-Myc), and caspase 1 (ICE) whereas upregulated the expression levels of CD95, p21, p53, and interleukin-13 (IL-13). Additionally, the protein expression levels of CD95 and Caspase 8 were significantly decreased after ILF2 overexpression while were significantly increased after ILF2 knock-down (P < 0.05). ILF2 knock-down may inhibit cell viability and promote cell apoptosis of hBVSMCs by regulating the expression levels of apoptosis-related genes and suppressing inflammatory response.


Assuntos
Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Proteína do Fator Nuclear 45/fisiologia , Apoptose/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Caspase 8/biossíntese , Caspase 8/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Técnicas de Silenciamento de Genes , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/metabolismo , Transfecção , Vasculite/metabolismo , Receptor fas/biossíntese , Receptor fas/genética
9.
Dis Markers ; 2020: 5514145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299497

RESUMO

Background: Tumor necrosis factor-α (TNF-α) is a proinflammatory factor involved in the pathogenesis of immunoglobulin A vasculitis (IgAV). The association between serum TNF-α and disease severity in adult patients with IgAV nephritis (IgAV-N) has been inadequately evaluated. Methods: Serum TNF-α was measured by chemiluminescence immunoassay in 53 renal biopsy-proved IgAV-N patients, 53 healthy controls, and 53 IgA nephropathy (IgAN) patients. The correlations of clinicopathologic parameters of IgAV-N patients with serum TNF-α were analyzed. Results: In this cross-sectional study, the median age of IgAV-N patients was 29 (25-37) years, and 67.9% were female. Serum TNF-α was significantly higher in the IgAV-N group than in the healthy group [7.4 (5.7-9.4) pg/mL vs. 5.9 (5.0, 7.1) pg/mL, P = 0.001], but comparable with sex, age, and estimated glomerular filtration rate (eGFR) grade-matched IgAN patients. Serum creatinine (P = 0.006) and serum cystatin C (P = 0.001) were positively correlated with serum TNF-α level, while albumin (P = 0.014) and eGFR (P = 0.021) were negatively correlated with serum TNF-α level. Multivariate linear regression analysis revealed that eGFR (P = 0.007) was an independent clinical predictor of serum TNF-α. Patients with higher pathological classification grade also had higher serum TNF-α. Conclusions: Serum TNF-α is associated with renal function and the pathological classification of adult patients with IgAV-N. TNF-α is a potential biomarker for the assessment of IgAV-N severity.


Assuntos
Biomarcadores/sangue , Glomerulonefrite por IGA/fisiopatologia , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima , Vasculite/fisiopatologia , Adulto , Estudos de Casos e Controles , Creatinina/sangue , Estudos Transversais , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/metabolismo , Humanos , Modelos Lineares , Medições Luminescentes , Masculino , Índice de Gravidade de Doença , Vasculite/sangue , Vasculite/metabolismo , Adulto Jovem
10.
Int J Mol Sci ; 21(23)2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33291346

RESUMO

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.


Assuntos
COVID-19/complicações , COVID-19/fisiopatologia , Células Endoteliais/patologia , SARS-CoV-2/fisiologia , Trombose/etiologia , Vasculite/etiologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Células Endoteliais/metabolismo , Humanos , SARS-CoV-2/isolamento & purificação , Trombose/metabolismo , Trombose/fisiopatologia , Vasculite/metabolismo , Vasculite/fisiopatologia
11.
Int J Mol Sci ; 21(21)2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33142805

RESUMO

Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1's immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition-the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery-the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.


Assuntos
Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Vasculite/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Vasculite/tratamento farmacológico , Vasculite/imunologia , Vasculite/metabolismo
12.
Exp Mol Med ; 52(10): 1715-1729, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33028948

RESUMO

Hyperglycemia-mediated endothelial inflammation participates in the pathogenesis of cardiovascular complications in subjects with diabetes. Previous studies reported that phosphatase and tensin homolog deleted on chromosome ten (PTEN) and SET8 participate in high glucose-mediated endothelial inflammation. In this study, we hypothesize that SET8 regulates PTEN expression, thus contributing to high glucose-mediated vascular endothelial inflammation. Our data indicated that plasma soluble intercellular adhesion molecule-1 (sICAM-1) and endothelial selectin (e-selectin) were increased in patients with diabetes and diabetic rats. PTEN expression was augmented in the peripheral blood mononuclear cells of patients with diabetes and in the aortic tissues of diabetic rats. Our in vitro study indicated that high glucose increased monocyte/endothelial adhesion, endothelial adhesion molecule expression and p65 phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose led to endothelial inflammation via upregulation of PTEN. Furthermore, high glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. SET8 overexpression reversed the effects of high-glucose treatment. shSET8-mediated endothelial inflammation was counteracted by siPTEN. Furthermore, SET8 was found to interact with FOXO1. siFOXO1 attenuated high glucose-mediated endothelial inflammation. FOXO1 overexpression-mediated endothelial inflammation was counteracted by siPTEN. H4K20me1 and FOXO1 were enriched in the PTEN promoter region. shSET8 increased PTEN promoter activity and augmented the positive effect of FOXO1 overexpression on PTEN promoter activity. Our in vivo study indicated that SET8 was downregulated and FOXO1 was upregulated in the peripheral blood mononuclear cells of patients with diabetes and the aortic tissues of diabetic rats. In conclusion, SET8 interacted with FOXO1 to modulate PTEN expression in vascular endothelial cells, thus contributing to hyperglycemia-mediated endothelial inflammation.


Assuntos
Endotélio Vascular/metabolismo , Glucose/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , PTEN Fosfo-Hidrolase/genética , Adulto , Idoso , Animais , Biomarcadores , Glicemia , Células Cultivadas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Proteína Forkhead Box O1 , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Ratos , Vasculite/etiologia , Vasculite/metabolismo , Vasculite/patologia
13.
J Investig Med High Impact Case Rep ; 8: 2324709620966446, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33090049

RESUMO

A 76-year-old Caucasian male with a history of rheumatoid arthritis, Raynaud's phenomenon, pulmonary embolism on warfarin, and a previous amputation of his left partial ring and fifth finger presented with acute onset of rash in bilateral lower extremities. He was recently started on trimethoprim-sulfamethoxazole due to concern for cellulitis. Differential diagnosis for acute-onset rash with the patient's history presented as a challenge to the internist, as the differential is broad. Our case goes through the differential diagnosis to contrast the different presentations of rash in a patient with vasculitis. Ultimately skin biopsy in conjunction with a past positive cryoglobulinemic level helped confirm the diagnosis of cutaneous vasculitis, following which he was started on appropriate treatment and recovered.


Assuntos
Artrite Reumatoide/complicações , Crioglobulinas/metabolismo , Vasculite/complicações , Vasculite/metabolismo , Idoso , Artrite Reumatoide/patologia , Diagnóstico Diferencial , Exantema/patologia , Hospitais Rurais , Humanos , Masculino , Vasculite/patologia
14.
Biosci Rep ; 40(10)2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33030503

RESUMO

Bone morphogenetic protein-2 (BMP-2) is commonly applied in spinal surgery to augment spinal fusion. Nevertheless, its pro-inflammatory potential could induce dangerous side effects such as vascular hyper-permeability, posing the need for manners against this condition. The present study aims to investigate the protective effect of Zanthoxylum nitidum (ZN) on BMP-2-related hyperpermeability and inflammation on the human umbilical vein endothelial cells (HUVECs). The results revealed that, in a concentration-dependent manner, BMP-2 enhanced the production of pro-inflammatory cytokines, including interleukin (IL)-1α, IL-1ß, and tumor necrosis factor-α, which were, however, suppressed by ZN. ZN inhibited BMP-2-induced inflammatory response by suppressing the phosphorylation of NF-κBp65 and IκB, and the abnormal nuclear translocation of p65. Moreover, the inhibited expression intercellular tight junction protein VE-cadherin and Occludin caused by BMP-2 was blocked by ZN. The hyper-permeability of HUVECs induced by BMP-2, as expressed as the higher fluorescent intensity of dextran, was also reversed by ZN. Overall, these findings demonstrated that ZN antagonized BMP-2-induced inflammation and hyperpermeability. It could be a therapeutic candidate for the treatment of BMP-2-induced side effects during spinal fusion.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína Morfogenética Óssea 2/toxicidade , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vasculite/prevenção & controle , Zanthoxylum , Anti-Inflamatórios/isolamento & purificação , Células Cultivadas , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Fosforilação , Extratos Vegetais/isolamento & purificação , Vasculite/metabolismo , Vasculite/patologia , Zanthoxylum/química
15.
Arthritis Rheumatol ; 72(12): 2136-2146, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32627966

RESUMO

OBJECTIVE: In prevous studies, we established a new animal model, KLF5+/- ;Fli-1+/- mice, in which fundamental pathologic features of systemic sclerosis (SSc) are broadly recapitulated. SSc vasculopathy is believed to occur as a result of impaired vascular remodeling, but its detailed mechanism of action remains unknown. To address this, the present study investigated the properties of dermal microvascular endothelial cells (DMECs), bone marrow-derived endothelial progenitor cells (BM-EPCs), and bone marrow-derived mesenchymal stem cells (BM-MSCs), a precursor of pericytes, in KLF5+/- ;Fli-1+/- mice. METHODS: Neovascularization and angiogenesis were assessed in KLF5+/- ;Fli-1+/- mice by in vivo Matrigel plug assay and in vitro tube formation assay, respectively. The properties of mouse BM-EPCs and BM-MSCs were assessed with in vitro studies. Dermal vasculature was visualized in vivo by injecting the mice with fluorescein isothiocyanate-conjugated dextran. RESULTS: Neovascularization was diminished in skin-embedded Matrigel plugs from KLF5+/- ;Fli-1+/- mice. DMECs from KLF5+/- ;Fli-1+/- mice showed defective tubulogenic activity, decreased expression of VE-cadherin and CD31, and an imbalance in the expression of Notch1/Dll4, suggesting that angiogenesis and anastomosis are disturbed. KLF5+/- ;Fli-1+/- mouse BM-MSCs exhibited enhanced proliferation and migration and increased collagen production following stimulation with transforming growth factor ß1, indicating that these cells differentiate preferentially into myofibroblasts rather than pericytes. KLF5+/- ;Fli-1+/- mouse BM-EPCs displayed a transition toward mesenchymal cells, suggesting that vasculogenesis is impaired. Wound healing was delayed in KLF5+/- ;Fli-1+/- mice (mean ± SD healing time 15.67 ± 0.82 days versus 13.50 ± 0.84 days; P = 0.0017), and the vascular network was poorly developed in wound scar tissue. CONCLUSION: The characteristics observed in the KLF5+/- ;Fli-1+/- mouse model - specifically, impaired neovascularization and vascular maturation - are similar to those observed in human SSc, and could be at least partially attributable to the induction of SSc-like properties in DMECs, BM-EPCs, and BM-MSCs. These findings indicate the critical contribution of Klf5 and Fli1 deficiency in vascular cells and related cell precursors to the development of SSc vasculopathy.


Assuntos
Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Mesenquimais/metabolismo , Neovascularização Patológica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Escleroderma Sistêmico/metabolismo , Vasculite/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Fatores de Transcrição Kruppel-Like/genética , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Proteína Proto-Oncogênica c-fli-1/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Vasculite/genética , Vasculite/patologia
16.
J Am Heart Assoc ; 9(12): e015513, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32476536

RESUMO

Background Aberrant activation of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP3 ubiquitination blunts the assembly and activation of the NLRP3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low-density lipoprotein receptor- or apolipoprotein E-deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP3 ubiquitination. We showed that tranilast restricted NLRP3 oligomerization and inhibited NLRP3 inflammasome assembly. Tranilast markedly suppressed NLRP3 inflammasome activation in low-density lipoprotein receptor- and apolipoprotein E-deficient macrophages. Through reconstitution of the NLRP3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP3 inflammasome activation. By adopting different regimens for tranilast treatment of low-density lipoprotein receptor- and apolipoprotein E-deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP3 ubiquitination, blunts the assembly and activation of the NLRP3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low-density lipoprotein receptor- and apolipoprotein E-deficient mice.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aterosclerose/prevenção & controle , Inflamassomos/metabolismo , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Vasculite/prevenção & controle , ortoaminobenzoatos/farmacologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos Knockout para ApoE , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Ubiquitinação , Vasculite/metabolismo , Vasculite/patologia
17.
Theranostics ; 10(15): 6599-6614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32550892

RESUMO

Inflammatory conditions are associated with a variety of diseases and can significantly contribute to their pathophysiology. Neutrophils are recognised as key players in driving vascular inflammation and promoting inflammation resolution. As a result, neutrophils, and specifically their surface formyl peptide receptors (FPRs), are attractive targets for non-invasive visualization of inflammatory disease states and studying mechanistic details of the process. Methods: A small-molecule Formyl Peptide Receptor 2 (FPR2/ALX)-targeted compound was combined with two rhodamine-derived fluorescent tags to form firstly, a targeted probe (Rho-pip-C1) and secondly a targeted, pH-responsive probe (Rho-NH-C1) for in vivo applications. We tested internalization, toxicity and functional interactions with neutrophils in vitro for both compounds, as well as the fluorescence switching response of Rho-NH-C1 to neutrophil activation. Finally, in vivo imaging (fluorescent intravital microscopy [IVM]) and therapeutic efficacy studies were performed in an inflammatory mouse model. Results: In vitro studies showed that the compounds bound to human neutrophils via FPR2/ALX without causing internalization at relevant concentrations. Additionally, the compounds did not cause toxicity or affect neutrophil functional responses (e.g. chemotaxis or transmigration). In vivo studies using IVM showed Rho-pip-C1 bound to activated neutrophils in a model of vascular inflammation. The pH-sensitive ("switchable") version termed Rho-NH-C1 validated these findings, showing fluorescent activity only in inflammatory conditions. Conclusions: These results indicate a viable design of fluorescent probes that have the ability to detect inflammatory events by targeting activated neutrophils.


Assuntos
Corantes Fluorescentes/química , Microscopia Intravital/métodos , Neutrófilos/patologia , Receptores de Formil Peptídeo/metabolismo , Vasculite/patologia , Doença Aguda , Adulto , Idoso , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Rodaminas/química , Transdução de Sinais , Vasculite/diagnóstico por imagem , Vasculite/metabolismo , Adulto Jovem
18.
Commun Biol ; 3(1): 327, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581266

RESUMO

Chronic inflammation plays a crucial role in vascular calcification. However, only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. Here, we show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). Moreover, miR-135a-5p is demonstrated to be a key regulator of the TGFBR1/TAK1 pathway, which has been reported to be decreased in CKD rats. We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, ultimately resulting in the attenuation of vascular inflammation and calcification in CKD rats. Our findings provide advanced insights into the mechanisms underlying the development of inflammation in vascular calcification, and evidence that FXR activation could serve as a therapeutic strategy for retarding vascular calcification in CKD patients.


Assuntos
Calcinose/metabolismo , MicroRNAs/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Vasculite/metabolismo , Animais , Aorta/citologia , Calcinose/genética , Células Cultivadas , Feminino , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Músculo Liso Vascular/citologia , Osteogênese , Ratos Wistar , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Vasculite/genética , Vasculite/patologia
19.
Clin Sci (Lond) ; 134(5): 439-458, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32091078

RESUMO

Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE-/-) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/prevenção & controle , Ácidos Graxos Monoinsaturados/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Morfolinas/farmacologia , Vasculite/prevenção & controle , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Atorvastatina/farmacologia , Transporte Biológico/efeitos dos fármacos , Ceramidas/antagonistas & inibidores , Ceramidas/metabolismo , Glicoesfingolipídeos/antagonistas & inibidores , Glicoesfingolipídeos/metabolismo , Imunossupressores/farmacologia , Lipídeos/sangue , Lipídeos/farmacocinética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/prevenção & controle , Vasculite/metabolismo
20.
JCI Insight ; 5(3)2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32051336

RESUMO

Vascular inflammation is present in many cardiovascular diseases, and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data have shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here, we performed ChIP for the glucocorticoid receptor, followed by next-generation sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in upregulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Furthermore, we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway, Frzb, via a glucocorticoid response element gleaned from our genomic data. These results suggest a role for endothelial Wnt signaling modulation in states of vascular inflammation.


Assuntos
Endotélio Vascular/metabolismo , Receptores de Glucocorticoides/metabolismo , Via de Sinalização Wnt , Animais , Imunoprecipitação da Cromatina , DNA/metabolismo , Dexametasona/farmacologia , Endotélio Vascular/citologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Knockout , Família Multigênica , Ligação Proteica , Receptores de Glucocorticoides/efeitos dos fármacos , Vasculite/metabolismo
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