Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Vascul Pharmacol ; 136: 106818, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33227452

RESUMO

OBJECTIVE: Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. APPROACHES AND RESULTS: In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. CONCLUSIONS: Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Aortite/prevenção & controle , Inibidores do Fator Xa/farmacologia , Rivaroxabana/farmacologia , Remodelação Vascular/efeitos dos fármacos , Angiotensina II , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aortite/induzido quimicamente , Aortite/metabolismo , Aortite/patologia , Cloreto de Cálcio , Moléculas de Adesão Celular/metabolismo , Citocinas/metabolismo , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Knockout para ApoE , Estudos Retrospectivos , Transdução de Sinais
2.
Cardiovasc Toxicol ; 20(1): 82-99, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31183600

RESUMO

This study investigated whether the whole-plant aqueous extract of Crataegus aronia (C. aronia) could protect against or alleviate high-fat diet (HFD)-induced aortic vascular inflammation in rats by inhibiting the NLRP-3 inflammasome pathway and examined some mechanisms of action with respect to its antioxidant and hypolipidemic effects. Adult male Wistar rats were divided into five groups (n = 6/each): standard diet (10% fat) fed to control rats, control + C. aronia (200 mg/kg), HFD (40% fat), HFD + C. aronia, and HFD post-treated with C. aronia. The HFD was fed for 8 weeks and C. aronia was administered orally for 4 weeks. In addition, isolated macrophages from control rats were pre-incubated with two doses of C. aronia (25 and 50 µg/mL) with or without lipopolysaccharide (LPS) stimulation. Only in HFD-fed rats, co- and post-C. aronia therapy lowered circulatory levels of LDL-C and ox-LDL-c and aortic protein levels of LOX-1 and CD36. C. aronia also inhibited the nuclear accumulation of NF-κB and lowered protein levels of NLRP-3, caspase-1, and mature IL-1ß. In vitro, in the absence of ox-LDL-c, C. aronia led to reduced nuclear levels of NF-κB, ROS generation, and protein NLRP-3 levels, in both LPS-stimulated and unstimulated macrophages, in a dose-dependent manner. However, protein levels of LOX-1 were not affected by C. aronia in unstimulated cells. In conclusion, C. aronia inhibits the NLRP-3 inflammasome pathway, induced by HFD feeding in the aorta of rats, mainly by its hypolipidemic effect and in vitro, in LPS-stimulated macrophages, by its antioxidant effect.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Hipolipemiantes/farmacologia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Aortite/etiologia , Aortite/imunologia , Aortite/metabolismo , Aterosclerose/etiologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Células Cultivadas , Crataegus , Dieta Hiperlipídica , Modelos Animais de Doenças , Hipolipemiantes/isolamento & purificação , Inflamassomos/imunologia , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
J Nutr Biochem ; 53: 9-19, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29175142

RESUMO

The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively. There were no differences in body weight and food intake between the groups from both strains (Swiss and LDLr-KO mice). GTT and cholesterol levels were improved by FS in both mice models. Lipidomics showed an increase in ω3 (C18:3) content, meanwhile stearic acid (C18:0) was not detected in endothelial tissue in response to FS. Moreover, FS markedly decreased pro-inflammatory (IL-1ß, TNF-α, pIκBα, pIKKß) and unfolded protein response markers (ATF6 and GRP78) in aorta. In Swiss mice, GPR120 was partially involved in the ω3-mediated anti-inflammatory actions, disrupting TLR4 pathway, but not in LDLr-KO mice. Partial replacement of dietary saturated by unsaturated ω3 fatty acids contributes to inhibition of cardiovascular risk markers, pro-inflammatory cytokines and ER stress sensors and effectors in the aorta. However, downregulation of inflammation is not mediated by arterial GPR120 activation.


Assuntos
Aortite/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Óleo de Semente do Linho/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Aortite/metabolismo , Modelos Animais de Doenças , Dislipidemias/dietoterapia , Dislipidemias/fisiopatologia , Chaperona BiP do Retículo Endoplasmático , Ácidos Graxos Ômega-3/farmacologia , Óleo de Semente do Linho/química , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Obesidade/dietoterapia , Obesidade/fisiopatologia , Substâncias Protetoras/farmacologia , Receptores de LDL/genética
4.
Gen Physiol Biophys ; 36(3): 353-359, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28635612

RESUMO

The aim of the work was to study the delayed effect of lipopolysaccharide (LPS) administration on endothelial function of the aorta of rats with genetic hypertension. Further, the possibility to ameliorate LPS-induced changes by n-3 polyunsaturated fatty acids (n-3 PUFA) was tested. Rats received a bolus of 1 mg/kg LPS i.p.; n-3 PUFA were administered in the dose of 30 mg/kg daily for 10 days p.o.. Ten days after receiving of LPS, the body weight gain of rats was statistically lower compared to control rats (p < 0.05). n-3 PUFA administration to LPS rats had no effect on this parameter. The TBARS and NAGA concentrations in plasma were significantly increased in the LPS group (p < 0.05) and n-3 PUFA administration returned them to control values. In functional studies, phenylephrine (PE, 1 µmol/l) evoked contraction of aortas which was not statistically different among experimental groups. However, endothelium-dependent relaxation was depressed in the LPS group (p < 0.05) and n-3 PUFA slightly recovered it to control values. In conclusion, oxidative stress seems to be responsible for aortic endothelial dysfunction detected 10 days after administration of LPS to rats. n-3 PUFA slightly improved the function of the endothelium injured by LPS, probably thanks to their antioxidant properties. Prolonged administration of higher doses of n-3 PUFA should defend the vascular endothelium against detrimental effect of bacterial inflammation.


Assuntos
Aorta/efeitos dos fármacos , Aorta/imunologia , Aortite/induzido quimicamente , Aortite/imunologia , Ácidos Graxos Ômega-3/administração & dosagem , Lipopolissacarídeos , Animais , Aortite/prevenção & controle , Interações Medicamentosas , Hipertensão/imunologia , Masculino , Ratos , Ratos Endogâmicos SHR
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA