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1.
Eur Respir J ; 53(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30923189

RESUMO

Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension in male and female obese mice.We depleted endogenous oestrogen in leptin-deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2',4,6'-tetramethoxystilbene (TMS).ob/ob mice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated pulmonary hypertension in male ob/ob mice. Intra-thoracic fat from ob/ob mice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress, effects that are attenuated by both ANA and TMS.Obesity can induce pulmonary hypertension and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.


Assuntos
Estrogênios/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Hipertensão Arterial Pulmonar/enzimologia , Artéria Pulmonar/enzimologia , Anastrozol , Animais , Citocromo P-450 CYP1B1/genética , Estradiol/sangue , Feminino , Hidroxiestronas/urina , Hipóxia/complicações , Leptina/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Obesidade/genética , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/patologia , Estilbenos
2.
Int J Nephrol ; 2011: 297070, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21860794

RESUMO

Elevated FGF-23 is a predictor of mortality and is associated with LVH in CKD. It may be a biomarker or a direct toxin. We assessed the relationship between FGF-23 and LVH in CKD using CMRI. In vitro we studied the effect of phosphate, FGF-23, and Klotho on E-selectin and VCAM production in HUVECs. FGF-23 concentration correlates negatively with eGFR and positively with LVMI. FGF-23 was an independent predictor of LVH in CKD. E-selectin and VCAM production was elevated in HUVECs cultured in high phosphate with FGF-23 or Klotho. This effect was attenuated in cells exposed to both FGF-23 and Klotho. FGF-23 is an independent predictor of LVH as measured by CMRI. We show preliminary data which supports that FGF-23 is toxic resulting in activation of the vascular endothelium. We do not prove causality with elevated FGF-23 and LVH. Further research should ascertain if lowering levels of FGF-23 translates to improved clinical outcomes.

3.
Am J Pathol ; 179(2): 661-72, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21704009

RESUMO

Transforming growth factor (TGF)-ß is one of the main fibrogenic cytokines that drives the pathophysiology of progressive renal scarring. MicroRNAs (miRNAs) are endogenous non-coding RNAs that post-transcriptionally regulate gene expression. We examined the role of TGF-ß-induced expression of miR-21, miRNAs in cell culture models and miRNA expression in relevant models of renal disease. In vitro, TGF-ß changed expression of miR-21, miR-214, and miR-145 in rat mesangial cells (CRL-2753) and miR-214, miR-21, miR-30c, miR-200b, and miR-200c during induction of epithelial-mesenchymal transition in rat tubular epithelial cells (NRK52E). miR-214 expression was robustly modulated in both cell types, whereas in tubular epithelial cells miR-21 was increased and miR-200b and miR-200c were decreased by 58% and 48%, respectively, in response to TGF-ß. TGF-ß receptor-1 was found to be a target of miR-200b/c and was down-regulated after overexpression of miR-200c. To assess the differential expression of these miRNAs in vivo, we used the anti-Thy1.1 mesangial glomerulonephritis model and the unilateral ureteral obstruction model in which TGF-ß plays a role and also a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat with and without salt loading. The expressions of miR-214 and miR-21 were significantly increased in all in vivo models, showing a possible miRNA signature of renal damage despite differing causes.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Modelos Animais de Doenças , Glomerulonefrite/metabolismo , Hipertensão/patologia , Rim/lesões , Rim/metabolismo , Glomérulos Renais/metabolismo , Túbulos Renais/metabolismo , Masculino , Ratos , Ratos Endogâmicos WKY , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Ureter/patologia
4.
Atherosclerosis ; 191(2): 319-25, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16814295

RESUMO

To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.


Assuntos
Colesterol/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Adulto , Idoso , Colesterol/sangue , Relação Dose-Resposta a Droga , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Fluvastatina , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Indóis/farmacologia , Células K562 , Falência Renal Crônica/sangue , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/imunologia , Transplante de Rim , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Microdomínios da Membrana/metabolismo , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/imunologia , Projetos Piloto , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia
5.
Atherosclerosis ; 175(2): 305-13, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15262187

RESUMO

HMG-CoA reductase inhibitors (statins) block the mevalonate pathway, preventing biosynthesis of cholesterol and isoprenoids. We investigated the effect of simvastatin on lymphocytes from normal human subjects and cardiovascular disease patients in order to provide a model for the in vivo actions of statins. Thirteen healthy volunteers were treated with 40 mg per day of simvastatin following which mean total cholesterol was reduced by 23% (S.D.+/- 11.7%) and mean LDL-cholesterol by 36% (S.D.+/- 16.3%). Lymphocyte lipid raft levels, represented by Lyn and Fyn, were also reduced by simvastatin. Treatment with simvastatin did not alter ex vivo T-lymphocyte proliferation. However, the in vitro addition of 1 microM simvastatin reduced T-lymphocyte proliferation by 39% (S.D.+/- 18.1%) and a combination of prenyl transferase inhibitors reduced proliferation by 19% (S.D.+/- 22.7%). We also assessed the cytotoxicity of natural killer (NK) cells-a T-lymphocyte subset. NK cell cytotoxicity ex vivo was reduced by 30% (S.D.+/- 33.6%) following oral simvastatin treatment and by 56% (S.D.+/- 24.68%) after the in vitro addition of 1 microM simvastatin. Significant ex vivo reductions in T-cell proliferation and NK cell cytotoxicity were observed in patients with cardiovascular disease on treatment with statins. NK cells have been implicated in the pathogenesis of atherosclerosis, so the effect of statin therapy on NK cell cytotoxicity may contribute to the benefits of statins in cardiovascular disease.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Isquemia Miocárdica/sangue , Sinvastatina/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Administração Oral , Adulto , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Sinvastatina/administração & dosagem
6.
Atherosclerosis ; 172(2): 219-28, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15019531

RESUMO

Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.


Assuntos
Ácidos Graxos Monoinsaturados/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indóis/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Receptores de IgG/fisiologia , Transdução de Sinais/efeitos dos fármacos , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Arteriosclerose/metabolismo , Western Blotting , Células Cultivadas , Citometria de Fluxo , Fluvastatina , Interleucina-6/análise , Metaloproteinase 1 da Matriz/análise , Fosforilação , Tirosina/metabolismo
7.
Clin Exp Pharmacol Physiol ; 29(8): 673-8, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12099998

RESUMO

1. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) reduce serum cholesterol and have proven benefits in the treatment of cardiovascular disease. However, recent work suggests that statins may exert immunosuppressive effects in isolated lymphocytes and in solid organ transplant recipients. Fluvastatin does not interfere with the metabolism of commonly used immunosuppressive agents and, therefore, may have benefits in transplant recipients. 2. The aim of the present study was to investigate the potential immunomodulatory effects of fluvastatin in vitro in human lymphocytes and the underlying effects on signal transduction. 3. In vitro, fluvastatin (10 micromol/L) caused a time-dependent inhibition of T cell proliferation in response to cross-linking of CD3. 4. Thymidine incorporation was reduced by 22, 81 and 92% at days 1, 3 and 5, respectively. 5. Mevalonate (1 micromol/L) treatment for 4 or 24 h significantly reduced the inhibitory effects of fluvastatin; the reversal was abrogated by simultaneous exposure to mevalonate and a farnesyl transferase inhibitor. 6. At a subcellular level, fluvastatin treatment was associated with reduced functional activity of Ras-dependent extracellular signal-regulated kinase pathways and of Rho-dependent p38 activation. 7. These data suggest that the potential immunosuppressive actions of statins involve inhibition of subcellular pathways dependent on isoprenylation of signal peptides, including Ras, Rho and related G-proteins.


Assuntos
Ácidos Graxos Monoinsaturados/farmacologia , Inibidores do Crescimento/farmacologia , Imunossupressores/farmacologia , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Fluvastatina , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linfócitos T/citologia , Proteínas Quinases p38 Ativadas por Mitógeno
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