ABSTRACT
RESUMEN La Endotelina-1 (ET1) y Proteína C Reactiva ultrasensible (PCRus) como marcadores de disfunción endotelial (DE) e inflamación vascular en hipotiroidismo subclínico (HS) han mostrado resultados controvertidos. El rol del estrés oxidativo y defensa antioxidante (TRAP) es motivo de discusión. Objetivos Establecer si el HS y la autoinmunidad tiroidea (AIT), excluyendo otros factores de riesgo cardiovascular, pueden causar DE e inflamación vascular, evaluadas a través de ET1 y PCRus, respectivamente. Establecer si TRAP juega algún rol. Evaluar cambios en ET1 y PCRus luego del tratamiento con levotiroxina (LT4). Material y métodos Se evaluaron prospectivamente 70 pacientes divididos en 3 grupos: HS: 41 pacientes (T4 normal,TSH >4,2 y <10 mUI/L), AIT: 10 pacientes eutiroideos (TSH <4,2 mUI/L) con aTPO y/o aTg (+) y Control: 19 pacientes eutiroideos sin AIT. Se excluyeron otros factores de riesgo cardiovascular. Se midió basalmente ET1, PCRus y TRAP plasmáticos, y en HS bajo LT4 (n = 24): ET1 y PCRus. Resultados No hubo diferencias significativas en edad, IMC, perfil lipídico y TRAP. ET1 y PCRus fueron significativamente mayores en pacientes con HS (media ± DS 1,77 ± 0,85 pg/ml y 1,5 ± 0,6 mg/l vs. controles (0,8 ± 0,3 pg/ml y 0,5 ± 0,2 mg/l) p <0,0001 y <0,008 respectivamente. Del mismo modo en AIT (1,4 ± 0.4 pg/ml y 2,3 ± 1,3 mg/l) vs controles p <0,0001 y <0,034, respectivamente. La TSH fue mayor en el grupo AIT vs. Control 2,57 ± 0,88 vs. 1,64 ± 0,5 mUI/L; p = 0,002. En HS bajo LT4 (8,7 ± 3,8 meses) se observó descenso de ET1 (p <0,001). ET1 correlacionó con TSH (r = 0,5 p <0,0001). El punto de corte de ET1 mediante curva ROC fue 1,32 pg/ml (Sensibilidad 81,6%-Especificidad 75%). Conclusiones ET1 y PCRus resultaron marcadores útiles para evaluar DE e inflamación vascular asociadas a HS. La defensa antioxidante no ejercería un rol en estos mecanismos. El tratamiento con LT4 produjo una significativa caída de ET1, pudiendo necesitarse un período más largo de eutiroidismo para normalizarla. En AIT, niveles de TSH >2,5 mUI/L podrían sugerir un mínimo grado de hipotiroidismo justificando la elevación en ET1 y PCR, sin descartar el rol de la AIT "per se".
ABSTRACT The measurement of endothelin-1 (ET1) and high sensitivity C-reactive protein (hsCRP) as markers of endothelial dysfunction (ED) and vascular inflammation in subclinical hypothyroidism (SH) has shown controversial results. The role of oxidative stress and antioxidant defense (TRAP) is a matter of discussion. Objectives To establish if SH and thyroid autoimmunity (TAI), excluding other cardiovascular risk factors, may cause ED and vascular inflammation, evaluated through the measurement of ET1 and hsCRP respectively. To determine if TRAP could have some role. Additionally, changes in these parameters after treatment with levothyroxine (LT4) will be evaluated. Material and methods: 70 patients were prospectively evaluated. They were classified into: SH Group: 41 patients (normal T4, TSH> 4.2 and <10 mIU/L), TAI Group: 10 euthyroid patients (TSH <4.2 mUI/L) with positive aTPO and/or aTg and Control Group: 19 euthyroid patients without TAI. Other cardiovascular risk factors were excluded in patients and controls. Plasma ET1, hsCRP and TRAP were measured basally, and ET1 and hsCRP under LT4 therapy in the HS Group. Results There were no significant differences between the 3 groups in age, BMI, lipids and TRAP. ET1 and hsCRP were significantly higher in patients with SH (mean ± SD 1.77 ± 0.85 pg/ml and 1.5 ± 0.6 mg/l) vs. controls (0.8 ± 0.3 pg/ml y 0.5 ± 0.2 mg/l) p <0.0001 y <0.008 respectively. Similarly, in TAI patients (1.4 ± 0.4 pg/ml y 2.3 ± 1.3 mg/l) vs controls, p <0.0001 and <0.034, respectively. TSH was higher in the TAI patients versus control group (2.5 ± 0.88 versus 1.64 ± 0.5 mIU/L, p = 0.002). Twenty-four patients with SH showed a significant decrease in ET1 (p <0.001) under treatment with LT4 (8.7 ± 3.8 months). ET1 had a highly significant correlation (p <0.0001) with TSH (r = 0.5). The cut-off level of ET1 established by ROC curve was 1.32 pg/ml (Sensitivity 81.6%-Specificity 75%). Conclusions ET1 and hsCRP were useful markers to evaluate ED and vascular inflammation associated with SH. There were no differences in TRAP levels between patients and controls, so it does not appear that oxidative stress would have played any role. Treatment with LT4 produced a significant drop in ET1. Probably, a longer period of euthyroidism might be necessary to normalize ET1 levels. In TAI Group, TSH levels >2.5 mUI/L could suggest a "minimal degree" of hypothyroidism justifying the elevation in ET1 and hs CRP. The role of the TAI "per se" couldn't be completely ruled out.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , C-Reactive Protein/drug effects , Endothelin-1/drug effects , Hypothyroidism/complications , Thyroxine/therapeutic use , C-Reactive Protein/analysis , Autoimmunity/drug effects , Case-Control Studies , Endothelin-1/analysis , Antioxidants/metabolismABSTRACT
Although 4,4'-diaminodiphenylsulfone (DDS, dapsone) has been used to treat several dermatologic conditions, including Hansen disease, for the past several decades, its mode of action has remained a topic of debate. We recently reported that DDS treatment significantly extends the lifespan of the nematode C. elegans by decreasing the generation of reactive oxygen species. Additionally, in in vitro experiments using non-phagocytic human fibroblasts, we found that DDS effectively counteracted the toxicity of paraquat (PQ). In the present study, we extended our work to test the protective effect of DDS against PQ in vivo using a mouse lung injury model. Oral administration of DDS to mice significantly attenuated the lung tissue damage caused by subsequent administration of PQ. Moreover, DDS reduced the local expression of mRNA transcripts encoding inflammation-related molecules, including endothelin-1 (ET-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and transforming growth factor-beta (TGF-beta). In addition, DDS decreased the PQ-induced expression of NADPH oxidase mRNA and activation of protein kinase Cmicro (PKCmicro). DDS treatment also decreased the PQ-induced generation of superoxide anions in mouse lung fibroblasts. Taken together, these data suggest the novel efficacy of DDS as an effective protective agent against oxidative stress-induced tissue damages.
Subject(s)
Animals , Male , Mice , Cells, Cultured , Chemokine CCL3/drug effects , Dapsone/administration & dosage , Endothelin-1/drug effects , Fibroblasts/drug effects , Herbicides/antagonists & inhibitors , Lung Injury/chemically induced , Mice, Inbred BALB C , Oxidative Stress , Paraquat/antagonists & inhibitors , Protective Agents/administration & dosage , Protein Kinase C/genetics , Superoxides/analysis , Transforming Growth Factor beta/drug effectsABSTRACT
Endothelin-1 [ET-1], a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ETB. An unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid [SA] are allosteric inhibitors of ET-1 binding to ETA receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, dihalosalicylic acid dimers were synthesized and tested as inhibitors of [[125]I] ET-1 binding to ETA receptors in rat embryonic cardiomyocyte [H9c2 cell] membranes in aim to development of new potential allosteric inhibitors of ET-1. Some dihalo- salicylic acid dimers synthesized in this study showed promising activity as inhibitor of [[125]I] ET-1 binding to ETA receptors in comparing with the dihalosalicylic acid reported in literature, the bromo substituted compound B showed very interesting activity than other halogen substituted dimers, it causes about 40% inhibition at 100 microM and causes 100% inhibition at 500 microM. we conclude that dihalosalicylic acid dimers can mediate good inhibition activity in comparison to sole dihalosalicylic acid molecule
Subject(s)
Allosteric Site , Receptors, G-Protein-Coupled , Salicylic Acid , Endothelin-1/drug effects , Myocytes, Cardiac , Aspirin/analogs & derivatives , Salicylic AcidABSTRACT
Endothelin-1 [ET-1], a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ATB. A unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid [SA] are allosteric inhibitors of ET-1 binding to ETA receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, dihalosalicylic acid dimers were synthesized and tested as inhibitors of [[125]I] ET-1 binding to ETA receptors in rat embryonic cardiomyocyte [H9c2 cell] membranes in aim to development of new potential allosteric inhibitors of ET-1. Some dihalosalicylic acid dimers synthesized in this study showed promising activity as inhibitor of [[125]I] ET-1 binding to ETA receptors in comparing with the dihalosalicylic acid reported in literature. The bromo substituted compound b showed more remarkable activity than other halogen substituted dimers, it causes about 40% inhibition at 100 microM and causes 100% inhibition at 500 microM. We conclude that dihalosalicylic acid dimers can mediate good inhibition activity in comparison to sole dihalosalicylic acid molecule