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1.
Medicine (Baltimore) ; 100(7): e24695, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607810

RESUMO

RATIONALE: Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels. PATIENT CONCERNS: A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery. DIAGNOSES: We diagnosed the patient as having acute aortic thrombosis caused by cisplatin. INTERVENTIONS: The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin. OUTCOMES: One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage. LESSONS: Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.


Assuntos
Doenças da Aorta/patologia , Cisplatino/toxicidade , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Trombose/induzido quimicamente , Administração Intravenosa , Administração Oral , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Antineoplásicos/toxicidade , Carcinoma de Células Escamosas/tratamento farmacológico , Produtos de Degradação da Fibrina e do Fibrinogênio/efeitos dos fármacos , Heparina/administração & dosagem , Heparina/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias/métodos , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Varfarina/administração & dosagem , Varfarina/uso terapêutico
2.
Nutr Metab Cardiovasc Dis ; 31(1): 344-353, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500110

RESUMO

BACKGROUND AND AIMS: Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE-/- mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability. METHODS AND RESULTS: In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet administration. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease. CONCLUSIONS: The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies.


Assuntos
Doenças da Aorta/etiologia , Aterosclerose/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/patologia , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Fibrose , Lipídeos/sangue , Camundongos Knockout para ApoE , Placa Aterosclerótica , Ruptura Espontânea , Vitamina D/sangue , Deficiência de Vitamina D/sangue
5.
Arterioscler Thromb Vasc Biol ; 41(2): 651-667, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33327742

RESUMO

OBJECTIVE: HDL (high-density lipoprotein) particles are known to possess several antiatherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant, and anti-inflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Approach and Results: Eight-week-old EKO mice, EKO mice overexpressing human apoA-I, and wild-type mice as controls were fed either normal laboratory or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated, and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyze the transcriptome of the aorta of the 3 genotypes in each experimental condition. In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system, and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway. CONCLUSIONS: ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response.


Assuntos
Aorta/metabolismo , Doenças da Aorta/genética , Apolipoproteína A-I/metabolismo , Aterosclerose/genética , Inflamação/genética , Lisossomos/genética , Esfingolipídeos/metabolismo , Transcriptoma , Animais , Aorta/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/metabolismo , Inflamação/patologia , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Mapas de Interação de Proteínas , Transdução de Sinais , Esfingolipídeos/sangue , Fatores de Tempo , Triglicerídeos/sangue
6.
Arterioscler Thromb Vasc Biol ; 41(2): e112-e127, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33327743

RESUMO

OBJECTIVE: Hyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on TSP-1 (thrombospondin-1) expression, a proatherogenic matricellular protein implicated in atherogenesis. However, a causal role of TSP-1 in leptin-driven atherosclerosis remains unknown. Approach and Results: Seventeen-weeks-old ApoE-/- and TSP-1-/-/ApoE-/- double knockout mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5 µg/g bwt, IP) once daily for 3 weeks. Using aortic root morphometry and en face lesion assay, we found that TSP-1 deletion abrogated leptin-stimulated lipid-filled lesion burden, plaque area, and collagen accumulation in aortic roots of ApoE-/- mice, shown via Oil red O, hematoxylin and eosin, and Masson trichrome staining, respectively. Immunofluorescence microscopy of aortic roots showed that TSP-1 deficiency blocked leptin-induced inflammatory and smooth muscle cell abundance as well as cellular proliferation in ApoE-/- mice. Moreover, these effects were concomitant to changes in VLDL (very low-density lipoprotein)-triglyceride and HDL (high-density lipoprotein)-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB (phospho-cyclic AMP response element-binding protein) accompanied with augmented smooth muscle-myosin heavy chain expression in aortic vessels of leptin-treated double knockout versus leptin-treated ApoE-/-; also confirmed in aortic smooth muscle cells from the mice genotypes, incubated ± leptin in vitro. Finally, TSP-1 deletion impeded plaque burden in leptin-treated ApoE-/- on western diet, independent of plasma lipid alterations. CONCLUSIONS: The present study provides evidence for a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis. Our findings suggest a regulatory role of TSP-1 on leptin-induced vascular smooth muscle cell phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Trombospondina 1/deficiência , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Colágeno/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Leptina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica , Transdução de Sinais , Trombospondina 1/genética
7.
Arterioscler Thromb Vasc Biol ; 41(2): e82-e96, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33356389

RESUMO

OBJECTIVE: Atherosclerotic lesions are often characterized by accumulation of OxLDL (oxidized low-density lipoprotein), which is associated with vascular inflammation and lesion vulnerability to rupture. Extracellular AIBP (apolipoprotein A-I binding protein; encoded by APOA1BP gene), when secreted, promotes cholesterol efflux and regulates lipid rafts dynamics, but its role as an intracellular protein in mammalian cells remains unknown. The aim of this work was to determine the function of intracellular AIBP in macrophages exposed to OxLDL and in atherosclerotic lesions. Approach and Results: Using a novel monoclonal antibody against human and mouse AIBP, which are highly homologous, we demonstrated robust AIBP expression in human and mouse atherosclerotic lesions. We observed significantly reduced autophagy in bone marrow-derived macrophages, isolated from Apoa1bp-/- compared with wild-type mice, which were exposed to OxLDL. In atherosclerotic lesions from Apoa1bp-/- mice subjected to Ldlr knockdown and fed a Western diet, autophagy was reduced, whereas apoptosis was increased, when compared with that in wild-type mice. AIBP expression was necessary for efficient control of reactive oxygen species and cell death and for mitochondria quality control in macrophages exposed to OxLDL. Mitochondria-localized AIBP, via its N-terminal domain, associated with E3 ubiquitin-protein ligase PARK2 (Parkin), MFN (mitofusin)1, and MFN2, but not BNIP3 (Bcl2/adenovirus E1B 19-kDa-interacting protein-3), and regulated ubiquitination of MFN1 and MFN2, key components of mitophagy. CONCLUSIONS: These data suggest that intracellular AIBP is a new regulator of autophagy in macrophages. Mitochondria-localized AIBP augments mitophagy and participates in mitochondria quality control, protecting macrophages against cell death in the context of atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Lipoproteínas LDL/toxicidade , Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Fosfoproteínas/metabolismo , Racemases e Epimerases/metabolismo , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/patologia , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/patologia , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Modelos Animais de Doenças , Células HEK293 , Células Hep G2 , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosfoproteínas/genética , Racemases e Epimerases/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
Am J Physiol Heart Circ Physiol ; 320(1): H52-H65, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33373275

RESUMO

Vascular cells restructure extracellular matrix in response to aging or changes in mechanical loading. Here, we characterized collagen architecture during age-related aortic remodeling in atherosclerosis-prone mice. We hypothesized that changes in collagen fiber orientation reflect an altered balance between passive and active forces acting on the arterial wall. We examined two factors that can alter this balance, endothelial dysfunction and reduced smooth muscle cell (SMC) contractility. Collagen fiber organization was visualized by second-harmonic generation microscopy in aortic adventitia of apolipoprotein E (apoE) knockout (KO) mice at 6 wk and 6 mo of age on a chow diet and at 7.5 mo of age on a Western diet (WD), using image analysis to yield mean fiber orientation. Adventitial collagen fibers became significantly more longitudinally oriented with aging in apoE knockout mice on chow diet. Conversely, fibers became more circumferentially oriented with aging in mice on WD. Total collagen content increased significantly with age in mice fed WD. We compared expression of endothelial nitric oxide synthase and acetylcholine-mediated nitric oxide release but found no evidence of endothelial dysfunction in older mice. Time-averaged volumetric blood flow in all groups showed no significant changes. Wire myography of aortic rings revealed decreases in active stress generation with age that were significantly exacerbated in WD mice. We conclude that the aorta displays a distinct remodeling response to atherogenic stimuli, indicated by altered collagen organization. Collagen reorganization can occur in the absence of altered hemodynamics and may represent an adaptive response to reduced active stress generation by vascular SMCs.NEW & NOTEWORTHY The following major observations were made in this study: 1) aortic adventitial collagen fibers become more longitudinally oriented with aging in apolipoprotein E knockout mice fed a chow diet; 2) conversely, adventitial collagen fibers become more circumferentially oriented with aging in apoE knockout mice fed a high-fat diet; 3) adventitial collagen content increases significantly with age in mice on a high-fat diet; 4) these alterations in collagen organization occur largely in the absence of hemodynamic changes; and 5) circumferential reorientation of collagen is associated with decreased active force generation (contractility) in aged mice on a high-fat diet.


Assuntos
Aorta Abdominal/patologia , Aorta Torácica/patologia , Doenças da Aorta/patologia , Aterosclerose/patologia , Dieta Ocidental , Colágenos Fibrilares/metabolismo , Remodelação Vascular , Fatores Etários , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/fisiopatologia , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/fisiopatologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Knockout para ApoE , Vasoconstrição
9.
Am J Physiol Heart Circ Physiol ; 319(4): H730-H743, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795184

RESUMO

Insulin-like growth factor-1 (IGF-1) decreases atherosclerosis in apolipoprotein E (Apoe)-deficient mice when administered systemically. However, mechanisms for its atheroprotective effect are not fully understood. We generated endothelium-specific IGF-1 receptor (IGF1R)-deficient mice on an Apoe-deficient background to assess effects of IGF-1 on the endothelium in the context of hyperlipidemia-induced atherosclerosis. Endothelial deficiency of IGF1R promoted atherosclerotic burden, when animals were fed on a high-fat diet for 12 wk or normal chow for 12 mo. Under the normal chow feeding condition, the vascular relaxation response to acetylcholine was increased in the endothelial IGF1R-deficient aorta; however, feeding of a high-fat diet substantially attenuated the relaxation response, and there was no difference between endothelial IGF1R-deficient and control mice. The endothelium and its intercellular junctions provide a barrier function to the vasculature. In human aortic endothelial cells, IGF-1 upregulated occludin, claudin 5, VE-cadherin, JAM-A, and CD31 expression levels, and vice versa, specific IGF1R inhibitor, picropodophyllin, an IGF1R-neutralizing antibody (αIR3), or siRNA to IGF1R abolished the IGF-1 effects on junction and adherens proteins, suggesting that IGF-1 promoted endothelial barrier function. Moreover, endothelial transwell permeability assays indicated that inhibition of IGF-1 signaling elevated solute permeability through the monolayer of human aortic endothelial cells. In summary, endothelial IGF1R deficiency increases atherosclerosis, and IGF-1 positively regulates tight junction protein and adherens junction protein levels and endothelial barrier function. Our findings suggest that the elevation of the endothelial junction protein level is, at least in part, the mechanism for antiatherogenic effects of IGF-1.NEW & NOTEWORTHY Endothelial insulin-like growth factor-1 (IGF-1) receptor deficiency significantly elevated atherosclerotic burden in apolipoprotein E-deficient mice, mediated at least in part by downregulation of intercellular junction proteins and, thus, elevated endothelial permeability. This study revealed a novel role for IGF-1 in supporting endothelial barrier function. These findings suggest that IGF-1's ability to promote endothelial barrier function may offer a novel therapeutic strategy for vascular diseases such as atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Permeabilidade Capilar , Células Endoteliais/metabolismo , Receptor IGF Tipo 1/deficiência , Animais , Antígenos CD/metabolismo , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Caderinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/patologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Células THP-1 , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
10.
Arterioscler Thromb Vasc Biol ; 40(9): 2070-2083, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32762445

RESUMO

OBJECTIVE: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar-/-/Apoe-/- mice were generated by cross-breeding of atherosclerosis-prone Apoe-/- mice and C3ar-/- mice. C3ar-/-/Apoe-/- mice and Apoe-/- mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b+ leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe-/- mice, C3ar-/-/Apoe-/- mice developed more severe atherosclerosis. In addition, C3ar-/-/Apoe-/- mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. CONCLUSIONS: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis-mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Inflamação/prevenção & controle , Macrófagos Peritoneais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiotaxia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Fenótipo , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Vascul Pharmacol ; 133-134: 106777, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750408

RESUMO

Atherosclerosis is a systemic chronic inflammatory disease. Many antioxidants including alpha-lipoic acid (LA), a product of lipoic acid synthase (Lias), have proven to be effective for treatment of this disease. However, the question remains whether LA regulates the immune response as a protective mechanism against atherosclerosis. We initially investigated whether enhanced endogenous antioxidant can retard the development of atherosclerosis via immunomodulation. To explore the impact of enhanced endogenous antioxidant on the retardation of atherosclerosis via immune regulation, our laboratory has recently created a double mutant mouse model, using apolipoprotein E-deficient (Apoe-/-) mice crossbred with mice overexpressing lipoic acid synthase gene (LiasH/H), designated as LiasH/HApoe-/- mice. Their littermates, Lias+/+Apoe-/- mice, served as a control. Distinct redox environments between the two strains of mice have been established and they can be used to facilitate identification of antioxidant targets in the immune response. At 6 months of age, LiasH/HApoe-/- mice had profoundly decreased atherosclerotic lesion size in the aortic sinus compared to their Lias+/+Apoe-/- littermates, accompanied by significantly enhanced numbers of regulatory T cells (Tregs) and anti-oxidized LDL autoantibody in the vascular system, and reduced T cell infiltrates in aortic walls. Our results represent a novel exploration into an environment with increased endogenous antioxidant and its ability to alleviate atherosclerosis, likely through regulation of the immune response. These outcomes shed light on a new therapeutic strategy using antioxidants to lessen atherosclerosis.


Assuntos
Aorta/enzimologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Placa Aterosclerótica , Sulfurtransferases/biossíntese , Animais , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/imunologia , Aterosclerose/patologia , Autoanticorpos/sangue , Modelos Animais de Doenças , Indução Enzimática , Lipoproteínas LDL/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Oxirredução , Estresse Oxidativo , Sulfurtransferases/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
12.
Arterioscler Thromb Vasc Biol ; 40(9): 2095-2107, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757647

RESUMO

OBJECTIVE: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of ß-VLDLs-the major atherogenic lipoproteins. ß-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than ß-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.


Assuntos
Doenças da Aorta/prevenção & controle , Apolipoproteína C-III/deficiência , Aterosclerose/prevenção & controle , Doença da Artéria Coronariana/prevenção & controle , Triglicerídeos/sangue , Animais , Animais Geneticamente Modificados , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteína C-III/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Lipoproteínas IDL/sangue , Fígado/metabolismo , Masculino , Oxirredução , Placa Aterosclerótica , Coelhos
13.
Vasc Health Risk Manag ; 16: 203-213, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606717

RESUMO

Aortic intramural hematoma (AIH) is an entity within the acute aortic syndrome. Combination of a priori probability, clinical history, laboratory blood test and imaging techniques are the basis for diagnosis of AIH. This review is focused on all aspects related to diagnosis of patients with AIH, from clinical to imaging and analytical.


Assuntos
Aorta , Doenças da Aorta/diagnóstico , Hematoma/diagnóstico , Aorta/diagnóstico por imagem , Aorta/patologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/patologia , Doenças da Aorta/terapia , Biomarcadores/sangue , Biópsia , Diagnóstico Diferencial , Hematoma/diagnóstico por imagem , Hematoma/patologia , Hematoma/terapia , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
16.
Arterioscler Thromb Vasc Biol ; 40(7): 1738-1747, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434411

RESUMO

OBJECTIVE: The extracellular matrix of atherosclerotic arteries contains abundant deposits of cellular Fn-EDA (fibronectin containing extra domain A), suggesting a functional role in the pathophysiology of atherosclerosis. Fn-EDA is synthesized by several cell types, including endothelial cells (ECs) and smooth muscle cells (SMCs), which are known to contribute to different stages of atherosclerosis. Although previous studies using global Fn-EDA-deficient mice have demonstrated that Fn-EDA is proatherogenic, the cell-specific role of EC versus SMC-derived-Fn-EDA in atherosclerosis has not been investigated yet. Approach and Results: To determine the relative contribution of different pools of Fn-EDA in atherosclerosis, we generated mutant strains lacking Fn-EDA in the ECs (Fn-EDAEC-KO) or smooth muscle cells (Fn-EDASMC-KO) on apolipoprotein E-deficient (Apoe-/-) background. The extent of atherosclerotic lesion progression was evaluated in whole aortae, and cross-sections of the aortic sinus in male and female mice fed a high-fat Western diet for either 4 weeks (early atherosclerosis) or 14 weeks (late atherosclerosis). Irrespective of sex, Fn-EDAEC-KO, but not Fn-EDASMC-KO mice, exhibited significantly reduced early atherogenesis concomitant with decrease in inflammatory cells (neutrophil and macrophage) and VCAM-1 (vascular cell adhesion molecule-1) expression levels within the plaques. In late atherosclerosis model, irrespective of sex, Fn-EDASMC-KO mice exhibited significantly reduced atherogenesis, but not Fn-EDAEC-KO mice, that was concomitant with decreased macrophage content within plaques. Lesional SMCs, collagen content, and plasma inflammatory cytokines (TNF-α [tumor necrosis factor-α] and IL-1ß [interleukin-1ß]), total cholesterol, and triglyceride levels were comparable among groups. CONCLUSIONS: EC-derived Fn-EDA contributes to early atherosclerosis, whereas SMC-derived Fn-EDA contributes to late atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Fibronectinas/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Citocinas/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/patologia , Feminino , Fibronectinas/deficiência , Fibronectinas/genética , Mediadores da Inflamação/sangue , Lipídeos/sangue , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Neutrófilos/metabolismo , Transdução de Sinais , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Am J Physiol Renal Physiol ; 318(5): F1188-F1198, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249611

RESUMO

Caloric restriction (CR) is known to have multiple beneficial effects on health and longevity. To study the effect of CR on phosphorus metabolism and vascular calcification (VC), rats were fed normal or restricted calories (67% of normal). The phosphorus content of the diets was adjusted to provide equal phosphorus intake independent of the calories ingested. After 50 days of CR, rats had negative phosphorus balance, lower plasma phosphorus, glucose, triglycerides, and leptin, and higher adiponectin than rats fed normal calories. Uremia was induced by 5/6 nephrectomy (Nx). After Nx, rats were treated with calcitriol (80 ng/kg ip every other day) and high-phosphorus diets (1.2% and 1.8%). No differences in aortic calcium content were observed between rats that ate normal or restricted calories before Nx in either rats that received 1.2% phosphorus (11.5 ± 1.7 vs. 10.9 ± 2.1 mg/g tissue) or in rats that received 1.8% phosphorus (12.5 ± 2.3 vs. 12.0 ± 2.9 mg/g of tissue). However, mortality was significantly increased in rats subjected to CR before Nx in both the 1.2% phosphorus groups (75% vs. 25%, P = 0.019) and 1.8% phosphorus groups (100% vs. 45%, P < 0.001). After calcitriol administration was stopped and phosphorus intake was normalized, VC regressed rapidly, but no significant differences in aortic calcium were detected between rats that ate normal or restricted calories during the regression phase (5.7 ± 2.7 and 5.2 ± 1.5 mg/g tissue). In conclusion, CR did not prevent or ameliorate VC and increased mortality in uremic rats.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Restrição Calórica , Rim/metabolismo , Fósforo na Dieta/metabolismo , Uremia/dietoterapia , Calcificação Vascular/prevenção & controle , Animais , Aorta/patologia , Doenças da Aorta/etiologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Calcitriol , Modelos Animais de Doenças , Progressão da Doença , Metabolismo Energético , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/metabolismo , Rim/patologia , Nefrectomia , Ratos Wistar , Fatores de Tempo , Uremia/etiologia , Uremia/metabolismo , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
18.
Cardiovasc Ther ; 2020: 1926249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32328171

RESUMO

Isoliquiritigenin (ISL) is a flavonoid isolated mainly from the licorice plant, a traditional Chinese herb. ISL has shown anticancer, anti-inflammatory, antioxidant, and antidiabetic activities. However, the pharmaceutical effects of ISL on atherosclerosis are seldom explored. In this study, we used apolipoprotein E (ApoE) knockout mouse model and angiotensin II- (Ang II-) stimulated vascular smooth muscle cells (VSMCs) to elucidate the pharmacological mechanism of ISL to inhibit atherosclerosis. We found that in ApoE-/- mice ISL could attenuate atherosclerotic lesion, reduce serum lipid levels, and inhibit TRPC5 expression. In vitro, ISL inhibited Ang II-stimulated proliferation of VSMCs and suppressed Ang II-induced TRPC5 and PCNA expressions in a dose-dependent fashion. In conclusion, our findings provide novel insight into the pharmacological effects of ISL on atherosclerosis and suggest that ISL is beneficial for cardiovascular protection.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Chalconas/farmacologia , Placa Aterosclerótica , Canais de Cátion TRPC/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais , Canais de Cátion TRPC/metabolismo
19.
Ann Vasc Surg ; 67: 338-345, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32234398

RESUMO

BACKGROUND: Penetrating ulcers of the abdominal aorta (PUAA) are an increasingly common finding on abdominal imaging studies; however, their significance and natural history are not well described. This study's objective was to analyze the demographics, presentation, and outcomes of patients with a radiographic diagnosis of PUAA. MATERIALS AND METHODS: Patients at our tertiary referral center were identified for inclusion based on a search for the term "penetrating ulcer" in abdominal computed tomography and magnetic resonance imaging reports between January 2014 and December 2017. Patients' electronic medical records were retrospectively reviewed to determine baseline medical characteristics, imaging indication, and subsequent clinical course, interventions, and outcomes. Aortic diameters and ulcer depths were measured by a single observer on initial and follow-up imaging to assess for association with concomitant aortic pathology, evolving aortic disease, and ulcer progression, defined as increase in depth of ≥ 1 mm. Statistical analysis was performed using STATA 16 (College Station, TX: StataCorp LLC), and a threshold P-value of <0.05 was set for significance. RESULTS: Ninety-two patients with PUAA were identified; 57 (62%) were male. The mean age at diagnosis was 79.3 years, and comorbidities included hypertension (74%), hyperlipidemia (65%), and malignancy (34%). The most common indication for imaging was chest, back, or abdominal pain (19%). On initial imaging, the mean ulcer depth was 1 cm (range from 0.2 cm to 3.4 cm). Concomitant abdominal aortic dilation ≥ 3 cm was found in 34 (37%) patients. Thirty-six (39%) patients had a vascular surgery consultation immediately after radiographic diagnosis. Follow-up axial imaging was performed on 27 (29%) untreated patients. The overall sample's mean ulcer depth remained essentially unchanged from initial measurement (P = 0.99); however, 14 (52%) patients with follow-up imaging were found to have increased overall aortic diameter. Of the total 92 patients, 9 (10%) underwent an endovascular abdominal aortic intervention during the review period: 2 for symptomatic PUAA and the remainder for progression of concomitant aneurysmal disease. All-cause mortality was 5% during the mean follow-up period of 21.9 months (range 0 to 72.5 months). Of the patients lost to follow-up, 61% did not receive vascular referral after initial diagnosis. CONCLUSIONS: PUAA are typically incidental findings identified in elderly, comorbid patients undergoing imaging for an unrelated indication. Although isolated findings of asymptomatic PUAA rarely require surgical intervention, these patients we argue would benefit from vascular surgery referral for long-term follow-up and interval imaging to assess for disease progression and concomitant aortic degeneration, which may necessitate repair. In addition, we observed that most of those patients lost to follow-up did not receive vascular consultation, suggesting that lack of involvement of vascular specialists at the time of diagnosis is a missed opportunity to secure appropriate follow-up and management.


Assuntos
Aorta Abdominal/cirurgia , Doenças da Aorta/cirurgia , Procedimentos Endovasculares , Encaminhamento e Consulta , Úlcera/cirurgia , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/mortalidade , Doenças da Aorta/patologia , Bases de Dados Factuais , Progressão da Doença , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Úlcera/diagnóstico por imagem , Úlcera/mortalidade , Úlcera/patologia
20.
BMC Cardiovasc Disord ; 20(1): 133, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169038

RESUMO

BACKGROUND: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process. METHODS: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays. RESULTS: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1ß, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression. CONCLUSION: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Placa Aterosclerótica , Pirazóis/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Aorta Abdominal/enzimologia , Aorta Abdominal/patologia , Doenças da Aorta/sangue , Doenças da Aorta/enzimologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/patologia , Citocinas/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Janus Quinase 2/metabolismo , Lipídeos/sangue , Masculino , Fosforilação , Coelhos , Transdução de Sinais
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