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1.
Adv Exp Med Biol ; 1131: 183-213, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646511

RESUMO

Ca2+ binding proteins (CBP) are of key importance for calcium to play its role as a pivotal second messenger. CBP bind Ca2+ in specific domains, contributing to the regulation of its concentration at the cytosol and intracellular stores. They also participate in numerous cellular functions by acting as Ca2+ transporters across cell membranes or as Ca2+-modulated sensors, i.e. decoding Ca2+ signals. Since CBP are integral to normal physiological processes, possible roles for them in a variety of diseases has attracted growing interest in recent years. In addition, research on CBP has been reinforced with advances in the structural characterization of new CBP family members. In this chapter we have updated a previous review on CBP, covering in more depth potential participation in physiopathological processes and candidacy for pharmacological targets in many diseases. We review intracellular CBP that contain the structural EF-hand domain: parvalbumin, calmodulin, S100 proteins, calcineurin and neuronal Ca2+ sensor proteins (NCS). We also address intracellular CBP lacking the EF-hand domain: annexins, CBP within intracellular Ca2+ stores (paying special attention to calreticulin and calsequestrin), proteins that contain a C2 domain (such as protein kinase C (PKC) or synaptotagmin) and other proteins of interest, such as regucalcin or proprotein convertase subtisilin kexins (PCSK). Finally, we summarise the latest findings on extracellular CBP, classified according to their Ca2+ binding structures: (i) EF-hand domains; (ii) EGF-like domains; (iii) ɣ-carboxyl glutamic acid (GLA)-rich domains; (iv) cadherin domains; (v) Ca2+-dependent (C)-type lectin-like domains; (vi) Ca2+-binding pockets of family C G-protein-coupled receptors.


Assuntos
Proteínas de Ligação ao Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Humanos , Espaço Intracelular/metabolismo
2.
Oxid Med Cell Longev ; 2019: 3086270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205584

RESUMO

The gut microbiota, the ecosystem formed by a wide symbiotic community of nonpathogenic microorganisms that are present in the distal part of the human gut, plays a prominent role in the normal physiology of the organism. The gut microbiota's imbalance, gut dysbiosis, is directly related to the origin of various processes of acute or chronic dysfunction in the host. Therefore, the ability to intervene in the gut microbiota is now emerging as a possible tactic for therapeutic intervention in various diseases. From this perspective, evidence is growing that a functional dietary intervention with probiotics, which maintain or restore beneficial bacteria of the digestive tract, represents a promising therapeutic strategy for interventions in cardiovascular diseases and also reduces the risk of their occurrence. In the present work, we review the importance of maintaining the balance of the intestinal microbiota to prevent or combat such processes as arterial hypertension or endothelial dysfunction, which underlie many cardiovascular disorders. We also review how the consumption of probiotics can improve autonomic control of cardiovascular function and provide beneficial effects in patients with heart failure. Among the known effects of probiotics is their ability to decrease the generation of reactive oxygen species and, therefore, reduce oxidative stress. Therefore, in this review, we specifically focus on this antioxidant capacity and its relationship with the beneficial cardiovascular effects described for probiotics.

3.
Curr Pharm Biotechnol ; 19(6): 483-494, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29938618

RESUMO

BACKGROUND: By acting on multiple targets and promoting diverse actions, angiotensin II (Ang II) plays a pivotal role in vascular function. Recent studies suggested that phosphodiesterase-5 (PDE-5) inhibitors exhibit therapeutic effects in cardiovascular diseases. Here, the effects of sildenafil on vascular disturbances were analyzed in a mouse model of Ang II-induced hypertension. METHODS AND RESULTS: Male C57BL/6 mice were used as untreated animals (control) or infused with Ang II (1000 ηg/kg/min) for 28 days and treated with sildenafil (40 mg/kg/min) or vehicle (Ang II) during the last two weeks. After 4 weeks, the Ang II animals exhibited a high systolic blood pressure (186±3 mmHg vs. 127±3 mmHg for control mice), which was attenuated by sildenafil (163±7 mmHg). The mesenteric vessels from the Ang II animals revealed damage to the endothelial layer, an increase in the cross-section area (1.9-fold) and vascular cell production of peroxynitrite (512±13 a.u.), which was ameliorated in the Ang II-Sil group (1.2-fold and 400±17 a.u.). Analysis of the vascular responsiveness showed an increased contractility response to norepinephrine in Ang II animals (Rmax: 70%), which was abolished by sildenafil through increased nitric oxide (NO) bioavailability and decreased reactive oxygen species (ROS) and vasoconstrictor prostanoids. CONCLUSION: Sildenafil attenuates the morphofunctional deleterious effects of Ang II on resistance vessels. The benefits of sildenafil seem to occur through restoring the balance of ROS/NO/eicosanoids. Therefore, this study opened new avenues for further clinical targeting of the treatment of cardiovascular diseases related to activation of the renin-angiotensin system.

4.
Cell Physiol Biochem ; 44(5): 1796-1809, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29216624

RESUMO

BACKGROUND/AIMS: The atherosclerotic apolipoprotein E-deficient (apoE-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. METHODS: Adult male apoE-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. RESULTS: ApoE-/- mice exhibited enhanced vasoconstriction to PE (Rmax ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE-/- mice also exhibited enhanced contractions to ET-1 (Rmax ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). CONCLUSION: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.


Assuntos
Apolipoproteínas E/genética , Ciclo-Oxigenase 1/metabolismo , Citrato de Sildenafila/farmacologia , Tromboxano A2/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Apolipoproteínas E/deficiência , Compostos Bicíclicos Heterocíclicos com Pontes , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ácidos Graxos Insaturados , Hidrazinas/farmacologia , Interleucina-10/análise , Interleucina-6/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrobenzenos/farmacologia , Fenilefrina/farmacologia , Pirazóis/farmacologia , Receptores de Tromboxanos/antagonistas & inibidores , Receptores de Tromboxanos/metabolismo , Sulfonamidas/farmacologia
5.
Ultrason Sonochem ; 37: 368-374, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28427645

RESUMO

Achyrocline satureioides or Macela, has been largely used in traditional folk medicine in Brazil as an anti-inflammatory agent and to treat various digestive disorders. The aim of the present study was to evaluate the preventive action of the extracts of A. satureioides obtained by maceration and ultrasound-assisted extraction, quercetin and N-acetylcysteine against contrast-induced nephropathy in mice. The antioxidant activity, cytotoxicity and inhibition of nitric oxide (NO) production in macrophages were evaluated. Also, chemical analyses of phenolic compounds, total flavonoids, and quercetin by LC-MS/MS present in various extracts of A. satureioides were performed. Thirty six mice were divided into six groups: control group (C), Contrast-Induced Nephropathy group (CIN), Group N-acetylcysteine 200mg/kg (NAC); Group quercetin 10mg/kg (Q), Group Macela 10mg/kg (M10), and Group Macela 50mg/kg (M50). The serum levels of urea and creatinine, advanced oxidation protein products (AOPP) and renal ultrastructure were evaluated by electron microscopy scanning. Ultrasound-assisted extraction improved the quality of extract (with 100% ethanol), since did not show toxicity to fibroblasts, and showed potent antioxidant activity and a high content of phenolic compounds, flavonoids, and quercetin, in addition to being able to reduce the production of NO in dose-dependent effect in macrophages. Results showed that animals treated with Macela extracts maintained normal levels of urea, creatinine, and AOPP, while preserving ultrastructure of the renal cells. The obtained results were more promising than NAC and Q groups in protecting against renal failure caused by CIN, showing that the plant can be a promising drug for preventing this disease.


Assuntos
Achyrocline/química , Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ondas Ultrassônicas , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Creatinina/sangue , Flavonoides/análise , Masculino , Camundongos , Óxido Nítrico/biossíntese , Fenóis/análise , Picratos/química , Extratos Vegetais/química , Quercetina/análise , Ureia/sangue
6.
Nutrition ; 35: 100-105, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28241975

RESUMO

OBJECTIVES: Kefir is obtained by the action of acidic bacteria and yeasts that exist in symbiotic association in kefir grains. Recently, this fermented milk drink has been recommended for the treatment of several clinical conditions, such as inflammatory, gastrointestinal, or cardiovascular-related diseases, or a combination of these diseases. However, its effects on atherosclerosis are not yet clear. The aim of this study was to prove that chronic treatment with a soluble, nonbacterial fraction of kefir could reduce the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLr-/-) mice. METHODS: LDLr-/- mice were divided into four groups as follows: RESULTS: The soluble, nonbacterial fraction of kefir reduced lipid deposition (P < 0.05) independent of hypercholesterolemia. Moreover, kefir was capable of diminishing the circulating proinflammatory intereukin (IL)-6 level and the ratio of tumor necrosis factor-α to IL-10 (50% and 42%, P < 0.05, respectively) and augmenting the antiinflammatory IL-10 level by approximately 74% (P < 0.05). CONCLUSIONS: Chronic treatment with a soluble nonbacterial fraction of kefir was able to decrease the lipid deposition in LDLr-/- hypercholesteremic mice, at least in part through modifying the circulating cytokine profile. The beneficial effects of kefir provide new perspectives for its use as an adjuvant in the prevention of atherosclerosis.


Assuntos
Aterosclerose/prevenção & controle , Hipercolesterolemia/dietoterapia , Kefir/análise , Receptores de LDL/genética , Animais , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta Hiperlipídica , Hipercolesterolemia/sangue , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Kefir/microbiologia , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Transgênicos , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/metabolismo
7.
Front Physiol ; 7: 211, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375490

RESUMO

AIMS: It has been previously shown that the probiotic kefir (a symbiotic matrix containing acid bacteria and yeasts) attenuated the hypertension and the endothelial dysfunction in spontaneously hypertensive rats (SHR). In the present study, the effect of chronic administration of kefir on the cardiac autonomic control of heart rate (HR) and baroreflex sensitivity (BRS) in SHR was evaluated. METHODS: SHR were treated with kefir (0.3 mL/100 g body weight) for 60 days and compared with non-treated SHR and with normotensive Wistar-Kyoto rats. Cardiac autonomic vagal (VT) and sympathetic (ST) tones were estimated through the blockade of the cardiac muscarinic receptors (methylatropine) and the blockade of ß1-adrenoceptor (atenolol). The BRS was evaluated by the tachycardia and bradycardia responses to vasoactive drug-induced decreases and increases in arterial blood pressure (BP), respectively. Additionally, spontaneous BRS was estimated by autoregressive spectral analysis. RESULTS: Kefir-treated SHR exhibited significant attenuation of basal BP, HR, and cardiac hypertrophy compared to non-treated SHR (12, 13, and 21%, respectively). Cardiac VT and ST were significantly altered in the SHR (~40 and ~90 bpm) compared with Wistar rats (~120 and ~30 bpm) and were partially recovered in SHR-kefir (~90 and ~25 bpm). SHR exhibited an impaired bradycardic BRS (~50%) compared with Wistar rats, which was reduced to ~40% in the kefir-treated SHR and abolished by methylatropine in all groups. SHR also exhibited a significant impairment of the tachycardic BRS (~23%) compared with Wistar rats and this difference was reduced to 8% in the SHR-kefir. Under the action of atenolol the residual reflex tachycardia was smaller in SHR than in Wistar rats and kefir attenuated this abnormality. Spectral analysis revealed increased low frequency components of BP (~3.5-fold) and pulse interval (~2-fold) compared with Wistar rats and these differences were reduced by kefir-treatment to ~1.6- and ~1.5-fold, respectively. Spectral analysis also showed an impairment of spontaneous BRS in SHR, but kefir-treatment caused only a tendency to reverse this result. CONCLUSIONS: The novelty of this study is that daily chronic consumption of a low dose of kefir reduced the impairment of the cardiac autonomic control of HR and of the impaired BRS in SHR.

8.
Clin Biochem ; 49(10-11): 762-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27087511

RESUMO

OBJECTIVES: This study compared serum cystatin C (CysC) with conventional biomarkers of renal function in terms of their ability to predict illness severity in patients in a mixed intensive care unit (ICU). The present study also tested the hypothesis that increased CysC could predict illness severity in different clinical conditions in adult patients admitted to the ICU. DESIGN AND METHODS: The performance of serum creatinine, urea and CysC, as well as the Glomerular Filtration Rate (GFR) estimates (Cockcroft-Gault/MDRD/Larsson and CKD-EPI Equations) in predicting illness severity was compared in 60 critically ill patients. Adult patients admitted to the hospital were screened for eligibility in this prospective and observational study. The mean patient age was 52±19years. The average APACHE II score was 9.5±6 for the entire sample. The patients were assigned to two different degrees of severity, and the internally derived cut off value was an APACHE II score<10 or ≥10. RESULTS: Both serum CysC and urea showed significant correlations with APACHE II, even after controlling for age. Urea and CysC levels, as well as the GFR estimated by the method of Larsson and Cockcroft-Gault, remained significantly increased in patients in the APACHEII ≥10 group. The ROC curve analyses indicated that both urea and CysC levels have high sensitivity and specificity in the prediction of illness severity using the APACHE II as a gold standard prognostic stratification system. Furthermore, CysC was more accurate than the Larsson, CKD-EPI CysC, CKD-EPI Cr-CysC, Cockcroft-Gault and CKD-EPI Cr CFR estimation methods compared with the MDRD method. Additionally, CysC was a good predictor in both young and old patients, whereas urea was not predictive of illness severity. CONCLUSIONS: Our findings suggest that CysC and GFR estimates (Larsson or CKD-EPI CysC methods) are good predictors of illness severity in adult patients hospitalized in a mixed ICU.


Assuntos
Biomarcadores/sangue , Creatinina/sangue , Cistatina C/sangue , Nefropatias/sangue , Adulto , Estado Terminal , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Unidades de Terapia Intensiva , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Índice de Gravidade de Doença
9.
Front Physiol ; 6: 247, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26388784

RESUMO

AIMS: Diabetic nephropathy (DN) is one of the most important causes of chronic renal disease, and the incidence of DN is increasing worldwide. Considering our previous report (Gomes et al., 2014) indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated anti-oxidative, anti-apoptotic and renoprotective effects in the C57BL/6J model of DN, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE(-/-)). METHODS: Streptozotocin was used to induce diabetes (100 mg/kg/day, 3 days) in male apoE(-/-) mice (8 week-old). After 6 weeks, the mice were randomly separated into DQ: diabetic apoE(-/-) mice treated with quercetin (10 mg/kg/day, 4 weeks, n = 8), DV: diabetic ApoE(-/-) mice treated with vehicle (n = 8) and ND: non-treated non-diabetic mice (n = 8). RESULTS: Quercetin treatment diminished polyuria (~30%; p < 0.05), glycemia (~25%, p < 0.05), normalized the hypertriglyceridemia. Moreover, this bioflavonoid diminished creatininemia (~30%, p < 0.01) and reduced proteinuria but not to normal levels. We also observed protective effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight/body weight. CONCLUSIONS: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical changes (decrease in glucose and triglycerides serum levels) and reduction of glomerulosclerosis. Thus, this study highlights the relevance of quercetin as an alternative therapeutic option for DN, including in diabetes associated with dyslipidemia.

10.
Curr Pharm Biotechnol ; 16(9): 823-31, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26059106

RESUMO

In translational medicine, the discovery of new drugs or new potential uses for currently available drugs is crucial for treating the resistant hypertension associated with renal artery stenosis. The phosphodiesterase 5 inhibitor sildenafil has been shown to reduce blood pressure and to improve the endothelium-dependent relaxation in the two kidney, one clip (2K1C) mouse model of renovascular hypertension. In the present study, we evaluated the effects of sildenafil (40 mg/kg/day for two weeks) on the endothelial structure and contractile function in mesenteric resistance arteries 28 days after clipping the renal artery. The data showed an enhanced vascular contractile response to norepinephrine in 2K1C hypertensive mice (56%) when compared with Sham mice, which was associated with increased oxidative stress and with a thinning of endothelial cells. Sildenafil treatment caused a significant amelioration in the enhanced contractile responsiveness (18%), which was associated to the recovery of the endothelial surface and abolishment of the oxidative stress. These data suggest that sildenafil could be considered a promising therapeutic option to manage endothelial dysfunction and hypertension in resistant patients.


Assuntos
Endotélio Vascular/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Citrato de Sildenafila/farmacologia , Vasodilatadores/farmacologia , Animais , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Hipertensão Renovascular/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
11.
Curr Pharm Biotechnol ; 16(6): 517-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25860063

RESUMO

Sildenafil ameliorates aortic relaxations in apolipoprotein E knockout (apoE) mice. Now, we tested the hypothesis that endothelial dysfunction (ED) in this model is characterized by contractile hyperresponsiveness to phenylephrine (PE) and that this abnormality may be repaired using sildenafil. The aortic rings were evaluated in apoE mice treated with sildenafil (apoE-sil, 40 mg/kg/day) and compared with apoE and wild-type (WT) mice administered with vehicle (veh). The apoE-veh mice exhibited an imbalance of nitric oxide and reactive oxygen species (NO/ROS) levels and an increased maximum response (Rmax, 20%) and sensitivity (7%) to PE, which were not modified by endothelial removal. Under the prostanoids blockade, vasocontraction was decreased more in apoE-veh (-37%) than in WT (-27%) and apoE-sil (-30%) mice. NADPH-oxidase blockade abolished the enhanced contractile responsiveness in apoE-veh (-33%), without effects in WT and apoE-sil groups. The atherosclerotic lesions and the imbalance of NO/ROS were reduced (40%) in apoE-sil mice. In conclusion, ED in apoE mice was characterized by decreased NO-bioavailability and contractile hyperresponsiveness, due to thromboxane and oxidative stress, and was normalized by sildenafil. The beneficial effects of this phosphodiesterase-5 inhibitor on ED and lipid deposition provide new insights for its use as adjuvant in the treatment of atherosclerosis.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Citrato de Sildenafila/administração & dosagem , Vasoconstrição/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Módulo de Elasticidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos , Vasodilatadores/administração & dosagem
12.
Lipids Health Dis ; 13: 184, 2014 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-25481305

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease in diabetic patients. Increasing evidence from studies in the rodents has suggested that this disease is associated with increased oxidative stress due to hyperglycemia. In the present study, we evaluated the renoprotective, anti-oxidative and anti-apoptotic effects of the flavonoid quercetin in C57BL/6J model of DN. METHODS: DN was induced by streptozotocin (STZ, 100 mg/kg/day, for 3 days) in adult C57BL/6J mice. Six weeks later, mice were divided into the following groups: diabetic mice treated with quercetin (DQ, 10 mg/kg/day, 4 weeks), diabetic mice treated with vehicle (DV) or non-treated non-diabetic (ND) mice. RESULTS: Quercetin treatment caused a reduction in polyuria (~45%) and glycemia (~35%), abolished the hypertriglyceridemia and had significant effects on renal function including, decreased proteinuria and high plasma levels of uric acid, urea and creatinine, which were accompanied by beneficial effects on the structural changes of the kidney including glomerulosclerosis. Flow cytometry showed a decrease in oxidative stress and apoptosis in DN mice. CONCLUSION: Taken together, these data show that quercetin effectively attenuated STZ-induced cytotoxicity in renal tissue. This study provides convincing experimental evidence and perspectives on the renoprotective effects of quercetin in diabetic mice and outlines a novel therapeutic strategy for this flavonoid in the treatment of DN.


Assuntos
Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Glicemia , Diabetes Mellitus Experimental/sangue , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Estresse Oxidativo
13.
J Transl Med ; 12: 250, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25223948

RESUMO

BACKGROUND: The clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance. METHODS: 2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB). RESULTS: The 2K1C mice exhibited normal plasma levels of Ang I, II and 1-7, whereas the intrarenal Ang I and II were increased (~35% and ~140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (~45%) and intrarenal (+15%) Ang 1-7. The 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil. CONCLUSION: These data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Inibidores da Fosfodiesterase 5/farmacologia , Angiotensinas/sangue , Animais , Pressão Sanguínea , Peso Corporal , Citometria de Fluxo , Frequência Cardíaca , Hipertensão Renovascular/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Estresse Oxidativo
14.
J Transl Med ; 12: 35, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24502628

RESUMO

BACKGROUND: Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity. METHODS: The experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained. RESULTS: Sildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). In addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice. CONCLUSIONS: Our data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.


Assuntos
Dano ao DNA , Hipertensão Renovascular/patologia , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/farmacologia , Sulfonas/farmacologia , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ensaio Cometa , Constrição Patológica/patologia , Constrição Patológica/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Purinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Artéria Renal/efeitos dos fármacos , Artéria Renal/fisiopatologia , Citrato de Sildenafila
15.
Lipids Health Dis ; 12: 128, 2013 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-23981672

RESUMO

BACKGROUND: It is well known that enhanced production of reactive oxygen species (ROS) leads to oxidative stress observed in atherosclerosis and that ROS can also cause damage in cellular macromolecules, including DNA. Considering previous report that sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), has antioxidant effects, in the present study we evaluated the effect of this drug on genotoxicity of blood mononuclear cells (MNC) and liver cells from atherosclerotic apolipoprotein E knockout mice (apoE(-/-)). METHODS: ROS production in MNC was evaluated by flow cytometry with the fluorescent dye dihydroethidium (DHE), a method that has been used to quantify the production of superoxide anion, and DNA damage was evaluated in both MNC and liver cells using the alkaline comet assay. Sildenafil-administered apoE(-/-) mice were compared with strain-matched mice administered with vehicle and with C57BL/6 wild-type (WT) mice. RESULTS: MNC from apoE(-/-) vehicle exhibited a 2-fold increase in production of superoxide anion in comparison with WT. In contrast, sildenafil-administered apoE(-/-) mice showed superoxide anion levels similar to those observed in WT mice. Similarly, MNC and liver cells from apoE(-/-) vehicle mice showed a 4-fold and 2-fold augmented DNA fragmentation compared with WT, respectively, and sildenafil-administered apoE(-/-) mice exhibited minimal DNA damage in those cells similar to WT mice. CONCLUSIONS: ApoE(-/-) mice chronically administered with sildenafil exhibited reduced levels of superoxide anion in MNC and less DNA fragmentation in MNC and liver cells, which are biomarkers of genotoxicity. Therefore, sildenafil may offer a new perspective to the use of PDE5 inhibitors to protect against DNA damage, in cells involved in the inflammatory and dyslipidemic processes that accompany atherosclerosis.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Superóxidos/antagonistas & inibidores , Animais , Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/patologia , Ensaio Cometa , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Lipoproteínas/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Purinas/farmacologia , Citrato de Sildenafila , Superóxidos/metabolismo , Triglicerídeos/sangue
16.
Int J Mol Sci ; 14(2): 3325-42, 2013 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-23385237

RESUMO

Recent evidence from apolipoprotein E-deficient (apoE-/-) mice shows that aging and atherosclerosis are closely associated with increased oxidative stress and DNA damage in some cells and tissues. However, bone marrow cells, which are physiologically involved in tissue repair have not yet been investigated. In the present study, we evaluated the influence of aging and hypercholesterolemia on oxidative stress, DNA damage and apoptosis in bone marrow cells from young and aged apoE-/- mice compared with age-matched wild-type C57BL/6 (C57) mice, using the comet assay and flow cytometry. The production of both superoxide and hydrogen peroxide in bone marrow cells was higher in young apoE-/- mice than in age-matched C57 mice, and reactive oxygen species were increased in aged C57 and apoE-/- mice. Similar results were observed when we analyzed the DNA damage and apoptosis. Our data showed that both aging and hypercholesterolemia induce the increased production of oxidative stress and consequently DNA damage and apoptosis in bone marrow cells. This study is the first to demonstrate a functionality decrease of the bone marrow, which is a fundamental extra-arterial source of the cells involved in vascular injury repair.

17.
J Transl Med ; 11: 3, 2013 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-23289368

RESUMO

BACKGROUND: Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE-/-) mice. METHODS: ApoE-/- mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage) were compared to the untreated apoE-/- and the wild-type (WT) mice.Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh) in all of the groups. In a separate set of experiments, the roles of NO and ROS in the relaxation response to ACh were evaluated by incubating the aortic rings with L-NAME (NO synthase inhibitor) or apocynin (NADPH oxidase inhibitor). In addition, the atherosclerotic lesions were quantified and superoxide production was assessed. RESULTS: Sildenafil restored the vasodilator response to acetylcholine (ACh) in the aortic rings of the apoE-/- mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three groups of mice and revealed an augmented participation of NO in the endothelium-dependent vasodilation in the sildenafil-treated animals. The normalized endothelial function in sildenafil-treated apoE-/- mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Moreover, morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta. CONCLUSION: This is the first study demonstrating the beneficial effects of chronic treatment with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous hypercholesterolemia. These data indicate that the main mechanism of the beneficial effect of sildenafil on the endothelial function appears to involve an enhancement of the NO pathway along with a reduction in oxidative stress.


Assuntos
Apolipoproteínas E/fisiologia , Endotélio Vascular/efeitos dos fármacos , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonas/farmacologia , Acetofenonas/farmacologia , Animais , Apolipoproteínas E/genética , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Purinas/farmacologia , Citrato de Sildenafila
18.
Cell Physiol Biochem ; 29(1-2): 143-52, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22415083

RESUMO

BACKGROUND: G-CSF is a critical regulator of hematopoietic cell proliferation, differentiation and survival. It has been reported that G-CSF attenuates renal injury during acute ischemia-reperfusion. In this study we evaluated the effects of G-CSF on the renal and cardiovascular systems of 2K1C hypertensive mice. METHODS: Male C57BL/6 mice were subjected to left renal artery clipping (2K1C) or sham operation and were then administered G-CSF (100 µg/kg/day) or vehicle for 14 days. RESULTS: Arterial pressure was higher in 2K1C + vehicle animals than in 2K1C + G-CSF (150±5 vs. 129±2 mmHg, p<0.01, n=8). Plasma angiotensin I, II and 1-7 concentrations were significantly increased in 2K1C + Vehicle when compared to the normotensive Sham group. G-CSF prevented the increase of these vasoactive peptides. The clipped kidney/contralateral kidney weight ratio showed a less atrophy of the ischemic kidney in the treated group (0.50±0.02 vs. 0.66±0.01, p<0.05). The infarction area in the clipped kidney was completely prevented in 7 out of 8 2K1C + G-CSF mice. Administration of G-CSF protected the clipped kidney from apoptosis. CONCLUSION: Our data indicate that G-CSF prevents kidney infarction and markedly attenuates the increases in plasma angiotensin levels and hypertension in 2K1C mice, reinforcing the protective effect of G-CSF on kidney ischemia.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Hipertensão Renovascular/prevenção & controle , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Hemodinâmica/efeitos dos fármacos , Rim/lesões , Rim/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Lipids Health Dis ; 10: 211, 2011 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-22082357

RESUMO

Since the early 1990s, several strains of genetically modified mice have been developed as models for experimental atherosclerosis. Among the available models, the apolipoprotein E-deficient (apoE⁻/⁻) mouse is of particular relevance because of its propensity to spontaneously develop hypercholesterolemia and atherosclerotic lesions that are similar to those found in humans, even when the mice are fed a chow diet. The main purpose of this review is to highlight the key achievements that have contributed to elucidating the mechanisms pertaining to vascular dysfunction in the apoE⁻/⁻ mouse. First, we summarize lipoproteins and atherosclerosis phenotypes in the apoE⁻/⁻ mouse, and then we briefly discuss controversial evidence relative to the influence of gender on the development of atherosclerosis in this murine model. Second, we discuss the main mechanisms underlying the endothelial dysfunction of conducting vessels and resistance vessels and examine how this vascular defect can be influenced by diet, aging and gender in the apoE⁻/⁻ mouse.


Assuntos
Envelhecimento , Apolipoproteínas E/deficiência , Dieta , Endotélio/fisiopatologia , Caracteres Sexuais , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/terapia , Modelos Animais de Doenças , Endotélio/enzimologia , Endotélio/metabolismo , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Hipercolesterolemia/terapia , Lipoproteínas/sangue , Camundongos , Camundongos Knockout , Estresse Oxidativo
20.
Lipids Health Dis ; 10: 155, 2011 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-21896159

RESUMO

BACKGROUND: Recent studies have highlighted the potential of cell therapy for atherosclerosis. The aim of this study was to evaluate the effects of mononuclear cell (MNC) therapy on the development of atherosclerotic lesions in the apolipoprotein E knockout (apoE KO) mouse. METHODS: We investigated vascular lipid deposition, vascular remodeling, oxidative stress, and endothelial nitric oxide synthase (eNOS) expression in apoE KO mice treated with spleen MNCs isolated from lacZ transgenic mice (apoE KO-MNC) for 8 weeks compared to untreated control mice (apoE KO). RESULTS: Histological analysis of aortas showed a significant reduction in the lipid deposition area in apoE KO-MNC mice compared to apoE KO mice (0.051 ± 0.004 vs 0.117 ± 0.016 mm², respectively, p < 0.01). In addition, vessel morphometry revealed that MNC therapy prevented the outward (positive) remodeling in apoE KO mice that is normally observed (apoE KO-MNC: 0.98 ± 0.07 vs apoE KO: 1.37 ± 0.09), using wild-type mice (C57BL/6J) as a reference. ApoE KO-MNC mice also have reduced production of superoxide anions and increased eNOS expression compared to apoE KO mice. Finally, immunohistochemistry analysis revealed a homing of endothelial progenitor cells (EPCs) in the aortas of apoE KO-MNC mice. CONCLUSION: MNC therapy attenuates the progression of atherosclerosis in the aortas of apoE KO mice. Our data provide evidence that the mechanism by which this attenuation occurs includes the homing of EPCs, a decrease in oxidative stress and an upregulation of eNOS expression.


Assuntos
Apolipoproteínas E/metabolismo , Aterosclerose/terapia , Transfusão de Leucócitos , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Progressão da Doença , Feminino , Imuno-Histoquímica , Leucócitos Mononucleares , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/prevenção & controle , Células-Tronco/patologia , Superóxidos/metabolismo , Regulação para Cima , beta-Galactosidase/genética
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