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1.
Acta Physiol (Oxf) ; 239(3): e14023, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37553856

RESUMO

AIM: In addition to functioning as an energy sensor switch, AMPK plays a key role in the maintenance of cardiovascular homeostasis. However, obesity disrupts AMPK signaling, contributing to endothelial dysfunction and cardiovascular disease. This study aimed to elucidate if a short-term dietary intervention consisting in replacing the high-fat diet with a standard diet for 2 weeks could reverse obesity-induced endothelial dysfunction via AMPK-CREB activation. METHODS: For this, 5-week-old male C57BL6J mice were fed a standard (Chow) or a high-fat (HF) diet for 8 weeks. The HF diet was replaced by the chow diet for the last 2 weeks in half of HF mice, generating 3 groups: Chow, HF and HF-Chow. Vascular reactivity and western-blot assays were performed in the thoracic aorta. RESULTS: Returning to a chow diet significantly reduced body weight and glucose intolerance. Relaxant responses to acetylcholine and the AMPK activator (AICAR) were significantly impaired in HF mice but improved in HF-Chow mice. The protein levels of AMPKα, p-CREB and antioxidant systems (heme oxygenase-1 (HO-1) and catalase) were significantly reduced in HF but normalized in HF-Chow mice. CONCLUSION: Improving dietary intake by replacing a HF diet with a standard diet improves AMPK-mediated responses due to the upregulation of the AMPK/CREB/HO-1 signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP , Doenças Vasculares , Camundongos , Masculino , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Regulação para Cima , Obesidade/metabolismo , Transdução de Sinais , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL
2.
Biofactors ; 49(6): 1106-1120, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37286331

RESUMO

The angiotensin II type 2 receptor (AT2R) exerts vasorelaxant, anti-inflammatory, and antioxidant properties. In obesity, its activation counterbalances the adverse cardiovascular effects of angiotensin II mediated by the AT1R. Preliminary results indicate that it also promotes brown adipocyte differentiation in vitro. Our hypothesis is that AT2R activation could increase BAT mass and activity in obesity. Five-week-old male C57BL/6J mice were fed a standard or a high-fat (HF) diet for 6 weeks. Half of the animals were treated with compound 21 (C21), a selective AT2R agonist, (1 mg/kg/day) in the drinking water. Electron transport chain (ETC), oxidative phosphorylation, and UCP1 proteins were measured in the interscapular BAT (iBAT) and thoracic perivascular adipose tissue (tPVAT) as well as inflammatory and oxidative parameters. Differentiation and oxygen consumption rate (OCR) in the presence of C21 was tested in brown preadipocytes. In vitro, C21-differentiated brown adipocytes showed an AT2R-dependent increase of differentiation markers (Ucp1, Cidea, Pparg) and increased basal and H+ leak-linked OCR. In vivo, HF-C21 mice showed increased iBAT mass compared to HF animals. Both their iBAT and tPVAT showed higher protein levels of the ETC protein complexes and UCP1, together with a reduction of inflammatory and oxidative markers. The activation of the AT2R increases BAT mass, mitochondrial activity, and reduces markers of tissue inflammation and oxidative stress in obesity. Therefore, insulin reduction and better vascular responses are achieved. Thus, the activation of the protective arm of the renin-angiotensin system arises as a promising tool in the treatment of obesity.


Assuntos
Tecido Adiposo Marrom , Receptor Tipo 2 de Angiotensina , Animais , Masculino , Camundongos , Adipócitos Marrons , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
3.
Clin Sci (Lond) ; 135(24): 2763-2780, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34854902

RESUMO

The aim of the present study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). Five-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1 mg/kg/day, in the drinking water), generating four groups: Chow C, Chow C21, HF C, and HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition and TGF-ß1 concentrations were determined in the abdominal aorta and the activity of metalloproteinases (MMP) 2 and 9 was analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, paralleled by an augmented ß-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-ß1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice. In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Imidazóis/farmacologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Rigidez Vascular/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Colágeno/metabolismo , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Fator de Crescimento Transformador beta1/sangue
4.
Nutrients ; 13(3)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808927

RESUMO

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the ß-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA.


Assuntos
Artérias/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Rigidez Vascular/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Artérias/fisiologia , Peso Corporal , Colágeno/metabolismo , Dieta Hiperlipídica , Gorduras Insaturadas na Dieta/farmacologia , Elastina , Ácidos Graxos/farmacologia , Distrofia Endotelial de Fuchs , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Ácido Oleico , Óleos de Plantas , Óleo de Girassol , Remodelação Vascular/efeitos dos fármacos
5.
Clin Sci (Lond) ; 135(9): 1145-1163, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33899912

RESUMO

Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Imidazóis/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Receptor B2 da Bradicinina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Doenças Vasculares/prevenção & controle , Animais , Aorta Torácica/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Cross-Talk , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo
6.
Int J Mol Sci ; 22(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379399

RESUMO

Fetal undernutrition programs cardiometabolic diseases, with higher susceptibility in males. The mechanisms implicated are not fully understood and may be related to sex differences in placental adaptation. To evaluate this hypothesis, we investigated placental oxidative balance, vascularization, glucocorticoid barrier, and fetal growth in rats exposed to 50% global nutrient restriction from gestation day 11 (MUN, n = 8) and controls (n = 8). At gestation day 20 (G20), we analyzed maternal, placental, and fetal weights; oxidative damage, antioxidants, corticosterone, and PlGF (placental growth factor, spectrophotometry); and VEGF (vascular endothelial growth factor), 11ß-HSD2, p22phox, XO, SOD1, SOD2, SOD3, catalase, and UCP2 expression (Western blot). Compared with controls, MUN dams exhibited lower weight and plasma proteins and higher corticosterone and catalase without oxidative damage. Control male fetuses were larger than female fetuses. MUN males had higher plasma corticosterone and were smaller than control males, but had similar weight than MUN females. MUN male placenta showed higher XO and lower 11ß-HSD2, VEGF, SOD2, catalase, UCP2, and feto-placental ratio than controls. MUN females had similar feto-placental ratio and plasma corticosterone than controls. Female placenta expressed lower XO, 11ß-HSD2, and SOD3; similar VEGF, SOD1, SOD2, and UCP2; and higher catalase than controls, being 11ß-HSD2 and VEGF higher compared to MUN males. Male placenta has worse adaptation to undernutrition with lower efficiency, associated with oxidative disbalance and reduced vascularization and glucocorticoid barrier. Glucocorticoids and low nutrients may both contribute to programming in MUN males.


Assuntos
Desenvolvimento Fetal , Feto/metabolismo , Desnutrição/complicações , Fenômenos Fisiológicos da Nutrição Materna , Fator de Crescimento Placentário/metabolismo , Placenta/metabolismo , Caracteres Sexuais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Peso Corporal , Feminino , Peroxidação de Lipídeos , Masculino , Desnutrição/sangue , Oxirredução , Gravidez , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
7.
Sci Rep ; 10(1): 2902, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076010

RESUMO

The experimental approach for the study of cardiometabolic disorders requires the use of animal models fed with commercial diets whose composition differs notably, even between diets used for control groups. While chow diets are usually made of agricultural by-products, purified low-fat diets (LF) contain a higher percentage of easy metabolizable carbohydrates, together with a reduced amount of polyunsaturated fatty acids, micronutrients and fiber, all associated with metabolic and vascular dysfunction. We hypothesize that the LF diet, commonly used in control animals, could promote adverse vascular and metabolic outcomes. To address this issue, 5-week-old male C57BL6J mice were fed with a standard (Chow) or a LF diet for 6 weeks. Changes in body weight, adiposity, biochemical parameters, systemic and aortic insulin sensitivity and endothelial function were recorded. LF diet did not modify body weight but significantly impaired systemic glucose tolerance and increased triglycerides and cholesterol levels. Endothelial function and aortic insulin sensitivity were significantly impaired in the LF group, due to a reduction of NO availability. These findings highlight the importance of selecting the proper control diet in metabolic studies. It may also suggest that some cardiometabolic alterations obtained in experimental studies using LF as a control diet may be underestimated.


Assuntos
Aorta Torácica/fisiologia , Dieta , Glucose/metabolismo , Homeostase , Acetilcolina/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Metabolismo dos Carboidratos/efeitos dos fármacos , Colesterol/metabolismo , Dieta com Restrição de Gorduras , Fibras na Dieta/farmacologia , Ácidos Graxos Insaturados/farmacologia , Glucose/administração & dosagem , Insulina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Fenilefrina/metabolismo , Solubilidade , Gordura Subcutânea/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
8.
Am J Nephrol ; 51(4): 294-303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32088716

RESUMO

BACKGROUND: Development of albuminuria and arterial stiffness in Munich Wistar Frömter (MWF) rats, a model of chronic kidney disease, is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction. Finerenone (FIN), a novel, nonsteroidal, potent, and selective mineralocorticoid receptor antagonist, improves endothelial dysfunction through enhancing nitric oxide (NO) bioavailability and decreasing superoxide anion levels due to an upregulation in vascular and renal superoxide dismutase activity. We hypothesize that FIN reduces arterial stiffness in this model associated to the reduction in albuminuria and matrix metalloproteinase (MMP)-2/9 activity. METHODS: Twelve-week-old MWF rats with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated with FIN (10 mg/kg/day, once-daily oral gavage) or with vehicle (control, C) for 4 weeks. RESULTS: Arterial stiffness was significantly higher in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN treatment significantly lowered ß-index, a measure of intrinsic stiffness independent of geometry, in MWF (ßMWF-FIN = 7.7 ± 0.4 vs. ßMWF-C = 9.2 ± 0.5, p < 0.05) positively correlating with urinary albumin excretion. Elastin fenestrae area in the internal elastic lamina of MA from MWF-FIN was significantly larger (+377%, p < 0.05). FIN increased plasma pro-MMP-2 and decreased plasma MMP-2 and MMP-9 activities, correlating with reductions in ß-index. MA from MWF-FIN exhibited higher NO bioavailability and reduced superoxide anion levels compared to MWF-C. CONCLUSION: FIN treatment reduces intrinsic arterial stiffness in MA from MWF rats associated with changes in elastin organization, normalization of MMP-2 and MMP-9 activities, and reduction of oxidative stress. Moreover, reduction of arterial stiffness correlates with reduction in albuminuria.


Assuntos
Albuminúria/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Naftiridinas/administração & dosagem , Insuficiência Renal Crônica/complicações , Rigidez Vascular/efeitos dos fármacos , Animais , Doenças Cardiovasculares/etiologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Artérias Mesentéricas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Insuficiência Renal Crônica/urina , Transdução de Sinais/efeitos dos fármacos
9.
J Nutr Biochem ; 78: 108342, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32004927

RESUMO

The activation of endoplasmic reticulum (ER) stress and a reduction of AMP-dependent protein kinase (AMPK) phosphorylation have been described in obesity. We hypothesize that a moderate caloric restriction (CR) might contribute to reducing ER stress and increasing AMPK phosphorylation in peripheral tissues from genetically obese Zucker fa/fa rats and in peripheral blood mononuclear cells (PBMCs). Zucker Lean and Zucker fa/fa rats were fed with chow diet either ad libitum (AL) (C, as controls) or 80% of AL (CR) for 2 weeks, giving rise to four experimental groups: Lean C, Lean CR, fa/fa C and fa/fa CR. CR significantly increased AMPK phosphorylation in the liver, perirenal adipose tissue (PRAT) and PBMCs from fa/fa rats but not in the subcutaneous AT (SCAT), suggesting a reduced response of SCAT to CR. Liver samples of fa/fa rats exhibited an increased mRNA expression of PERK, EIF-2α, XBP-1(s), Chop and caspase 3, which was significantly reduced by CR. PRAT exhibited an overexpression of Edem and PDIA-4 in fa/fa rats, but only PDIA-4 expression was reduced by CR. eIF-2α phosphorylation was significantly increased in all studied tissues from fa/fa rats and reduced by CR. A negative correlation was detected between p-AMPK and p-eIF-2α in the liver, PRAT and PBMCs from fa/fa rats but not in SCAT. This study shows that a moderate CR reduces ER stress and improves AMPK phosphorylation in several peripheral tissues and in circulating PBMCs, suggesting that alterations observed in PBMCs could reflect metabolic alterations associated with obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Restrição Calórica , Estresse do Retículo Endoplasmático , Leucócitos Mononucleares/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Peso Corporal , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Obesidade/metabolismo , Fosforilação , Ratos , Ratos Zucker
10.
Free Radic Biol Med ; 139: 35-45, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100477

RESUMO

Caloric restriction (CR) improves endothelial function through the upregulation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Moreover, hydrogen peroxide (H2O2) is upregulated in yeast subjected to CR. Our aim was to assess if mild short-term CR increases vascular H2O2 formation as a link with AMPK and eNOS activation. Twelve-week old Zucker obese (fa/fa) and control Zucker lean male rats were fed a standard chow either ad libitum (AL, n=10) or with a 20% CR (CR, n=10) for two weeks. CR significantly improved relaxation to ACh in fa/fa rats because of an enhanced endogenous production of H2O2 in aortic rings (H2O2 levels fa/faAL=0.5 ±â€¯0.05 nmol/mg vs. H2O2 levels fa/faCR=0.76 ±â€¯0.07 nmol/mg protein; p<0.05). Expression of mitochondrial superoxide dismutase (Mn-SOD) and total SOD activity were increased in aorta from fa/fa animals after CR. In cultured aortic endothelial cells, serum deprivation or 2-deoxy-d-glucose induced a significant increase in: i) superoxide anion and H2O2 levels, ii) p-AMPK/AMPK and p-eNOS/eNOS expression and iii) nitric oxide levels. This effect was reduced by catalase and strongly inhibited by Ca2+/calmodulin-dependent kinase II (CamkII) silencing. In conclusion, we propose that mild short-term CR might be a trigger of mechanisms aimed at protecting the vascular wall by the increase of H2O2, which then activates AMPK and nitric oxide release, thus improving endothelium-dependent relaxation. In addition, we demonstrate that CAMKII plays a key role in mediating CR-induced AMPK activation through H2O2 increase.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Restrição Calórica , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Obesidade/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Catalase/genética , Catalase/metabolismo , Desoxiglucose/farmacologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Zucker , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Vasodilatação
11.
Sci Rep ; 9(1): 599, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679477

RESUMO

Infusions of murtilla leaves exhibit antioxidant, analgesic, and anti-inflammatory properties. Several compounds that are structurally similar to madecassic acid (MA), a component of murtilla leaf extract (ethyl acetate extract, EAE), have been shown to inhibit protein tyrosine phosphatase 1B (PTP1P). The aim of this study was to evaluate if EAE and two compounds identified in EAE (MA and myricetin [MYR]) could have a beneficial effect on systemic and vascular insulin sensitivity and endothelial function in a model of diet-induced obesity. Experiments were performed in 5-week-old male C57BL6J mice fed with a standard (LF) or a very high-fat diet (HF) for 4 weeks and treated with EAE, MA, MYR, or the vehicle as control (C). EAE significantly inhibited PTP1B. EAE and MA, but not MYR, significantly improved systemic insulin sensitivity in HF mice and vascular relaxation to Ach in aorta segments, due to a significant increase of eNOS phosphorylation and enhanced nitric oxide availability. EAE, MA, and MYR also accounted for increased relaxant responses to insulin in HF mice, thus evidencing that the treatments significantly improved aortic insulin sensitivity. This study shows for the first time that EAE and MA could constitute interesting candidates for treating insulin resistance and endothelial dysfunction associated with obesity.


Assuntos
Dieta Hiperlipídica , Endotélio Vascular/efeitos dos fármacos , Myrtaceae/química , Obesidade/patologia , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Animais , Aorta/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Insulina/farmacologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Myrtaceae/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/metabolismo , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triterpenos/química , Triterpenos/metabolismo
12.
Front Pharmacol ; 9: 1131, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356804

RESUMO

Albuminuria is an early marker of renovascular damage associated to an increase in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic kidney disease (CKD), which exhibits endothelial dysfunction associated to low nitric oxide availability. We hypothesize that the new highly selective, non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C; MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic blood pressure (SBP) and albuminuria were determined the last day of treatment. Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF. Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C rings. These alterations were reversed by finerenone to W-C control levels due to an upregulation in phosphorylated Akt and eNOS, and an increase in NO availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein levels were observed in rings of MWF-FIN, without differences in p22phox, p47phox or catalase levels. Total SOD activity was increased in kidneys from MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through an enhancement in NO bioavailability and a decrease in superoxide anion levels due to an upregulation in SOD activity. This is associated with an increase in renal SOD activity and a reduction of albuminuria.

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