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2.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500172

RESUMO

A healthy dietary pattern and high quality nutrient intake reduce atherosclerotic cardiovascular disease risk. Red wine grape pomace (RWGP)-a rich natural source of dietary fiber and antioxidants-appears to be a potential functional food ingredient. The impact of a dietary supplementation with RWGP flour was evaluated in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice, a model of lethal ischemic heart disease. SR-B1 KO/ApoER61h/h mice were fed with atherogenic (high fat, cholesterol, and cholic acid, HFC) diet supplemented with: (a) 20% chow (HFC-Control), (b) 20% RWGP flour (HFC-RWGP), or (c) 10% chow/10% oat fiber (HFC-Fiber); and survival time was evaluated. In addition, SR-B1 KO/ApoER61h/h mice were fed for 7 or 14 days with HFC-Control or HFC-RWGP diets and plasma lipid levels, inflammation, oxidative damage, and antioxidant activity were measured. Atherosclerosis and myocardial damage were assessed by histology and magnetic resonance imaging, respectively. Supplementation with RWGP reduced premature death, changed TNF-α and IL-10 levels, and increased plasma antioxidant activity. Moreover, decreased atheromatous aortic and brachiocephalic plaque sizes and attenuated myocardial infarction and dysfunction were also observed. These results suggest that RWGP flour intake may be used as a non-pharmacological therapeutic approach, contributing to decreased progression of atherosclerosis, reduced coronary heart disease, and improved cardiovascular outcomes.


Assuntos
Antioxidantes/administração & dosagem , Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Suplementos Nutricionais , Frutas/química , Isquemia Miocárdica/prevenção & controle , Miocárdio/metabolismo , Estresse Oxidativo , Extratos Vegetais/administração & dosagem , Vitis/química , Ração Animal , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Dieta Aterogênica , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Lipídeos/sangue , Masculino , Camundongos Knockout para ApoE , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Miocárdio/patologia , Extratos Vegetais/sangue , Extratos Vegetais/isolamento & purificação , Placa Aterosclerótica , Receptores Depuradores Classe B/deficiência , Receptores Depuradores Classe B/genética , Fator de Necrose Tumoral alfa/sangue
3.
Biomed Res Int ; 2019: 2931831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392210

RESUMO

Background: The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the clinical benefit of terpenoids in humans are scarce. This systematic review and meta-analysis evaluated the effects of terpenoid administration on atherosclerotic lesion area in ApoE -/- mice. Methods: A comprehensive literature search using PubMed, Embase, and the Cochrane Library databases was performed to identify studies that assessed the effects of terpenoids on atherosclerosis in ApoE -/- mice. The primary outcome was atherosclerotic lesion area, and study quality was estimated using SYRCLE's risk of bias tool. Results: The meta-analysis included 25 studies. Overall, terpenoids significantly reduced atherosclerotic lesion area when compared to vehicle control (P<0.00001; SMD: -0.55; 95% CI: -0.72, -0.39). In terpenoid type and dose subgroup analyses, sesquiterpenoid (P=0.002; SMD -0.93; 95% CI: -1.52, -0.34), diterpenoid (P=0.01; SMD: -0.30; 95% CI: -0.54, -0.06), triterpenoid (P<0.00001; SMD: -0.66; 95% CI: -0.94, -0.39), tetraterpenoid (P<0.0001; SMD: -1.81; 95% CI: -2.70, -0.91), low dose (P=0.0001; SMD: -0.51; 95% CI: -0.76, -0.25), medium dose (P<0.0001; SMD: -0.48; 95% CI: -0.72, -0.24), and high dose (P=0.002; SMD: -1.07; 95% CI: -1.74, -0.40) significantly decreased atherosclerotic lesion area when compared to vehicle control. PROSPERO register number is CRD42019121176. Conclusion: Sesquiterpenoid, diterpenoid, triterpenoid, and tetraterpenoid have potential as antiatherosclerotic agents with a wide range of doses. This systematic review provides a reference for research programs aimed at the development of terpenoid-based clinical drugs.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Terpenos/farmacologia , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout para ApoE , PubMed
4.
J Vasc Res ; 56(4): 181-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266015

RESUMO

BACKGROUND: Coagulant factor Xa inhibitors (XaIs) are prescribed for patients with atrial fibrillation for years. METHODS: Human umbilical venous endothelial cells (HUVECs) were cultured with or without (w/wo) a XaI (rivaroxaban) under high glucose (HG: 22 mM). Endothelial senescence was investigated by assessing senescence-associated-ß-galactosidase (SA-ß-gal), p53, and telomere length. Endothelial function and atherosclerosis were examined by nitric oxide-related-products (NOx: NO2- and NO3-), O2-, endothelial NO synthase (eNOS), NADPH oxidase (p22phox), and ICAM1. PAR1 (protease-activated receptor 1) and PAR2, which were reported to regulate eNOS phosphorylation, were inhibited by small interfering RNAs (siRNAs). Thirty-two male dyslipidemic type 2 diabetic rats (ZFDM LepRfa/fa) were fed a high-cholesterol diet w/wo XaI (50 µg/day/kg) for 1-4 weeks. RESULTS: SA-ß-gal, p53, p21, and p16INK4a were increased by HG and restored by XaI (50 nM) in HUVECs. XaI restored telomerase activity and preserved telomere length. XaI suppressed O2-, p22phox, and ICAM1 and restored NOx and eNOS. XaI decreased PAR1 following elevation by HG, which was confirmed by PAR1 siRNA and PAR2 siRNA. In in vivo experiments, plasma glucose, total cholesterol, and triglycerides were increased for 4 weeks but were not changed by XaI. XaI decreased SA-ß-gal and telomerase and preserved telomere length in the aortic endothelium. XaI activated eNOS, inhibited p22phox, increased plasma NOx, and decreased O2-. CONCLUSION: Rivaroxaban prevents replicative senescence in HUVECs and aortic endothelial cells in dyslipidemic diabetic mice. It restores endothelial function and prevents the progression of atherosclerosis.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Rivaroxabana/farmacologia , Animais , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Glicemia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lipídeos/sangue , Óxido Nítrico/metabolismo , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Receptores Ativados por Proteinase/metabolismo , Transdução de Sinais , Telomerase/metabolismo
5.
Int J Cardiovasc Imaging ; 35(10): 1903-1911, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31209684

RESUMO

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects 1 in 250 people. Aortic stiffness, measured by pulse wave velocity (PWV), is an independent predictor for cardiovascular events. Young FH patients are a unique group with early vessel wall disease that may serve to elucidate the determinants of aortic stiffness. We hypothesized that young FH patients would have early changes in aortic stiffness compared to healthy, age- and sex-matched reference values. Thirty-three FH patients ( ≥ 7 years age; mean age 14.6 ± 3.3 years; 26/33 on statin therapy) underwent cardiac MRI. PWV was determined using propagation of flow waveform from aortic arch phase contrast images. Distensibility and aortic wall thickness (AWT) were measured at the ascending, proximal descending, and diaphragmatic aorta. Ventricular volumes and left ventricular (LV) myocardial mass were measured from 2D cine images. These parameters were compared to age- and sex-matched reference values. FH patients had significantly higher PWV (4.5 ± 0.8 vs. 3.5 ± 0.3 m/s; p < 0.001), aortic distensibility, and ascending aortic wall thickness (1.37 ± 0.18 vs. 1.30 ± 0.02 mm; p < 0.05) compared to reference. There was no difference in aortic area or descending aortic wall thickness between groups. Young FH patients had aortic changes with increased aortic pulse wave velocity in the setting of increased aortic distensibility, accompanied by increased thickness of the ascending aortic wall. Presence of these early findings in young patients despite the majority being on statin therapy support enhanced screening and aggressive treatment of familial hypercholesterolemia to prevent potential future cardiovascular events.


Assuntos
Aorta/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Hiperlipoproteinemia Tipo II/complicações , Imagem Cinética por Ressonância Magnética , Análise de Onda de Pulso , Rigidez Vascular , Adolescente , Fatores Etários , Aorta/fisiopatologia , Doenças da Aorta/etiologia , Doenças da Aorta/fisiopatologia , Doenças da Aorta/prevenção & controle , Aterosclerose/etiologia , Aterosclerose/fisiopatologia , Aterosclerose/prevenção & controle , Estudos de Casos e Controles , Criança , Estudos Transversais , Progressão da Doença , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Masculino , Fenótipo , Placa Aterosclerótica , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Remodelação Vascular
6.
Nutr Metab Cardiovasc Dis ; 29(3): 306-315, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30738642

RESUMO

BACKGROUND AND AIMS: Heparin-binding EGF-like growth factor (HB-EGF) is a representative EGF family member that interacts with EGFR under diverse stress environment. Previously, we reported that the HB-EGF-targeting using antisense oligonucleotide (ASO) effectively suppressed an aortic aneurysm in the vessel wall and circulatory lipid levels. In this study, we further examined the effects of the HB-EGF ASO administration on the development of hyperlipidemia-associated atherosclerosis using an atherogenic mouse model. METHODS AND RESULTS: The male and female LDLR deficient mice under Western diet containing 21% fat and 0.2% cholesterol content were cotreated with control and HB-EGF ASOs for 12 weeks. We observed that the HB-EGF ASO administration effectively downregulated circulatory VLDL- and LDL-associated lipid levels in circulation; concordantly, the HB-EGF targeting effectively suppressed the development of atherosclerosis in the aorta. An EGFR blocker BIBX1382 administration suppressed the hepatic TG secretion rate, suggesting a positive role of the HB-EGF signaling for the hepatic VLDL production. We newly observed that there was a significant improvement of the insulin sensitivity by the HB-EGF ASO administration in a mouse model under the Western diet as demonstrated by the improvement of the glucose and insulin tolerances. CONCLUSION: The HB-EGF ASO administration effectively downregulated circulatory lipid levels by suppressing hepatic VLDL production rate, which leads to effective protection against atherosclerosis in the vascular wall.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Hiperlipidemias/prevenção & controle , Lipoproteínas VLDL/sangue , Oligonucleotídeos Antissenso/administração & dosagem , Animais , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Colesterol/sangue , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Células Hep G2 , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/genética , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Triglicerídeos/sangue
7.
Clin Sci (Lond) ; 133(5): 629-643, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737255

RESUMO

Aims: The renin-angiotensin system (RAS) plays an important role in the pathophysiology of vascular diseases, especially as a mediator of inflammation and tissue remodelling. Alamandine (Ala1-angiotensin-(1-7)) is a new biologically active peptide from the RAS, interacting with Mas-related G-protein-coupled receptor member D. Although a growing number of studies reveal the cardioprotective effects of alamandine, there is a paucity of data on its participation in vascular remodelling associated events. In the present study, we investigated the effects of alamandine on ascending aorta remodelling after transverse aortic constriction (TAC) in mice. Methods and results: C57BL/6J male mice were divided into the following groups: Sham (sham-operated), TAC (operated) and TAC+ALA (operated and treated with alamandine-HPßCD (2-Hydroxypropyl-ß-cyclodextrin), 30 µg/kg/day, by gavage). Oral administration of alamandine for 14 days attenuated arterial remodelling by decreasing ascending aorta media layer thickness and the cells density in the adventitia induced by TAC. Alamandine administration attenuated ascending aorta fibrosis induced by TAC, through a reduction in the following parameters; total collagen deposition, expression collagen III and transforming growth factor-ß (TGF-ß) transcripts, matrix metalloproteinases (MMPs) activity and vascular expression of MMP-2. Importantly, alamandine decreased vascular expression of proinflammatory genes as CCL2, tumour necrosis factor α (TNF-α) and interleukin-1ß (IL-1ß), and was able to increase expression of MRC1 and FIZZ1, pro-resolution markers, after TAC surgery. Conclusion: Alamandine treatment attenuates vascular remodelling after TAC, at least in part, through anti-fibrotic and anti-inflammatory effects. Hence, this work opens new avenues for the use of this heptapeptide also as a therapeutic target for vascular disease.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Oligopeptídeos/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
8.
Arterioscler Thromb Vasc Biol ; 39(3): 432-445, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30626205

RESUMO

Objective- Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease-related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification. Approach and Results- We found that ApoE-/- Tlr2-/- genotype in mice suppressed high-fat diet-induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE-/- mice. However, TLR2 deficiency prohibited high-fat diet-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6-mediated RANKL (receptor activator of nuclear factor κB ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-κB (nuclear factor κB) dependent signaling mediated by ERK1/2. Conclusions- We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6-mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.


Assuntos
Aterosclerose/patologia , Calcinose/metabolismo , Calcinose/patologia , Condrogênese/fisiologia , Interleucina-6/fisiologia , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , Receptor 2 Toll-Like/fisiologia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Apolipoproteínas E/deficiência , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/prevenção & controle , Calcinose/genética , Células Cultivadas , Colesterol na Dieta/toxicidade , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/toxicidade , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoprotegerina/genética , Ligante RANK/genética , Distribuição Aleatória
9.
Cardiovasc Res ; 115(1): 243-254, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917052

RESUMO

Aims: Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR-/-), and LDLR-/- mice expressing apoB-100 only (LDLR-/- ApoB100/100) having a humanized lipoprotein profile. Methods and results: LDLR-/- mice were fed a high-fat diet (HFD) for 6 or 12 weeks and LDLR-/-ApoB100/100 mice a regular chow diet for 6 or 12 months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR-/- mice reduced total plasma cholesterol after 6 weeks of HFD and triglycerides in LDLR-/-ApoB100/100 mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR-/-ApoB100/100 mice as it increased plaque calcification. Moreover, ∼36% of Nrf2-/-LDLR-/-ApoB100/100 females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12 months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR-/-ApoB100/100 female mice at age of 12 months. Conclusions: Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR-/-ApoB100/100 mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death.


Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Hipercolesterolemia/complicações , Fator 2 Relacionado a NF-E2/deficiência , Placa Aterosclerótica , Fatores Etários , Animais , Aorta/patologia , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Aterosclerose/etiologia , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hipercolesterolemia/genética , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Receptores de LDL/deficiência , Receptores de LDL/genética , Triglicerídeos/sangue
10.
Thorac Cardiovasc Surg ; 67(6): 503-512, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30352477

RESUMO

BACKGROUND: Transplant vasculopathy (TV) is the main limiting factor for long-term graft survival characterized by fibrosis, myofibroblast, and smooth muscle cell (SMC) proliferation. Decoy oligodeoxynucleotide (dODN) against the transcription factor activator protein-1 (AP-1) might interfere with the expression of AV-related genes that govern neointima formation. METHODS: Aortic allografts from DBA/2 mice were incubated with control buffer, consensus, or mutated control AP-1 dODN and were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight [BW]) was administered daily. Explantation and histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. RESULTS: Intima-to-media (I/M) ratio and neointima formation were significantly reduced in the consensus AP-1 dODN treatment group by 37% (p < 0.05) and 67% (p < 0.01), respectively. SMC α-actin-2 staining and macrophage marker expression revealed a marked reduction in the neointima. I/M ratio was found to correlate with the number of tissue macrophages (p < 0.05). MMP and fibrosis marker expression were not significantly altered. CONCLUSION: Intraoperative AP-1dODN utilization might be a strategy to preserve graft function after transplantation.


Assuntos
Aorta/transplante , Doenças da Aorta/prevenção & controle , Sobrevivência de Enxerto , Oligodesoxirribonucleotídeos/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Modelos Animais de Doenças , Feminino , Fibrose , Hiperplasia , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neointima , Oligodesoxirribonucleotídeos/genética , Fatores de Tempo , Fator de Transcrição AP-1/genética , Remodelação Vascular
11.
Gen Thorac Cardiovasc Surg ; 67(5): 413-419, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30374810

RESUMO

OBJECTIVES: Calcification is one of the major postoperative problems after aortic allograft implantation. We hypothesized that phosphate binders, lanthanum carbonate and calcium carbonate inhibit calcification of implanted aortic allografts and verified this hypothesis using a rat model. METHODS: Aortas were harvested from 4-week-old Brown Norway rats and implanted into the subdermal space of 4-week-old Lewis rats. Twenty-seven recipient Lewis rats were divided into Group N, Group L, and Group C (9 rats per group), which were fed a normal diet, a normal diet containing 3% lanthanum carbonate, and a normal diet containing 3% calcium carbonate, respectively. Implanted aortic allografts were explanted 2 weeks later. Calcification of aortic allografts was evaluated using von Kossa staining and calcium content assay. Calcification score was defined in von Kossa staining as 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Serum calcium and phosphorus levels at euthanasia were measured. RESULTS: Calcification scores were 2.6, 1.2, and 0.8, and calcium content was 48.9, 15.8, and 8.9 mg/dry·g, in Groups N, L, and C, respectively. Calcification was significantly reduced in Groups L and C. Serum calcium level was 11.5, 12.2, and 13.5 mg/dl, and serum phosphorus level was 15.4, 12.5, and 11.7 mg/dl, in Groups N, L, and C, respectively. Serum calcium level in Group C was significantly higher than in the other two groups. CONCLUSIONS: Lanthanum carbonate and calcium carbonate significantly reduced calcification of implanted aortic allografts in young rats. Although calcium carbonate induced hypercalcemia, lanthanum carbonate has significant potential to inhibit calcification of implanted aortic allografts.


Assuntos
Doenças da Aorta/prevenção & controle , Lantânio/uso terapêutico , Calcificação Vascular/prevenção & controle , Aloenxertos , Animais , Aorta Abdominal/transplante , Aorta Torácica/transplante , Doenças da Aorta/sangue , Doenças da Aorta/patologia , Prótese Vascular , Cálcio/sangue , Carbonato de Cálcio/uso terapêutico , Masculino , Modelos Animais , Fósforo/sangue , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Transplante Homólogo , Calcificação Vascular/sangue , Calcificação Vascular/patologia
12.
Arterioscler Thromb Vasc Biol ; 38(12): 2780-2792, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571174

RESUMO

Objective- Monocyte-derived foam cells are one of the key players in the formation of atherosclerotic plaques. Adenosine receptors and extracellular adenosine have been demonstrated to modulate foam cell formation. ADK (adenosine kinase) is a major enzyme regulating intracellular adenosine levels, but its functional role in myeloid cells remains poorly understood. To enhance intracellular adenosine levels in myeloid cells, ADK was selectively deleted in novel transgenic mice using Cre-LoxP technology, and foam cell formation and the development of atherosclerotic lesions were determined. Approach and Results- ADK was upregulated in macrophages on ox-LDL (oxidized low-density lipoprotein) treatment in vitro and was highly expressed in foam cells in atherosclerotic plaques. Atherosclerotic mice deficient in ADK in myeloid cells were generated by breeding floxed ADK (ADKF/F) mice with LysM-Cre (myeloid-specific Cre recombinase expressing) mice and ApoE-/- (apolipoprotein E deficient) mice. Mice absent ADK in myeloid cells exhibited much smaller atherosclerotic plaques compared with controls. In vitro assays showed that ADK deletion or inhibition resulted in increased intracellular adenosine and reduced DNA methylation of the ABCG1 (ATP-binding cassette transporter G1) gene. Loss of methylation was associated with ABCG1 upregulation, enhanced cholesterol efflux, and eventually decreased foam cell formation. Conclusions- Augmentation of intracellular adenosine levels through ADK knockout in myeloid cells protects ApoE-/- mice against atherosclerosis by reducing foam cell formation via the epigenetic regulation of cholesterol trafficking. ADK inhibition is a promising approach for the treatment of atherosclerotic diseases.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adenosina Quinase/deficiência , Aorta/enzimologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Epigênese Genética , Células Espumosas/enzimologia , Camundongos Knockout para ApoE , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Quinase/genética , Animais , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Colesterol/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Feminino , Células Espumosas/patologia , Masculino , Camundongos Endogâmicos C57BL , Placa Aterosclerótica , Transdução de Sinais
13.
Cardiovasc Ther ; 36(6): e12476, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30378752

RESUMO

AIMS: Despite the therapeutic efficacy of statins and antiplatelet agents for atherosclerosis, monotherapy with each drug alone is often insufficient to achieve the patient's therapeutic goals. We previously showed that combined statin/antiplatelet agent/anti-tumor necrosis factor (TNF) agent therapy (pravastatin/sarpogrelate/etanercept) reduces atherosclerotic lesions by inhibiting TNF, an atherogenic cytokine that contributes to the progression of arteriosclerosis. In addition, our previous study showed that combined treatment with pravastatin and cilostazol is effective for reducing TNF-driven inflammation through anti-TNF activity. Therefore, in the present study, we evaluated the additive effects of combined pravastatin and cilostazol therapy on atherosclerotic progression using low-density lipoprotein receptor (LDLR) knockout (KO) mice. METHODS: Ten-week-old LDLR KO mice were fed a high-fat, high-cholesterol diet and orally administered pravastatin and cilostazol alone or in combination. Body weight, plasma lipid levels, and the levels of intracellular adhesion molecules and inflammatory cytokines were analyzed. In addition, aortas and aortic roots were stained with Oil Red O, and atherosclerotic plaques were quantified. RESULTS: The atherosclerotic plaques in the combined pravastatin and cilostazol treatment groups were significantly reduced compared to those in each drug monotherapy group. The combination therapy group also showed the downregulation of ICAM-1, MOMA-2, TNF, interleukin (IL)-6, triglyceride, total cholesterol, and low-density lipoprotein levels and the upregulation of high-density lipoprotein levels compared to those of the pravastatin- or cilostazol-treated groups. CONCLUSIONS: Our results suggest that combination therapy with pravastatin and cilostazol exerts beneficial effects by decreasing atherosclerotic lesion progression and improving the pro-inflammatory state in the vascular endothelium. These effects are mediated by the reduction in adhesion molecule expression, immune cell infiltration, and cytokine levels and the antiatherosclerotic modulation of serum cholesterol levels. Therefore, we conclude that combined treatment with pravastatin and cilostazol may be a more effective antiatherosclerotic strategy than treatment with either agent alone.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Cilostazol/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Pravastatina/farmacologia , Receptores de LDL/deficiência , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Moléculas de Adesão Celular/metabolismo , Colesterol na Dieta , Citocinas/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Quimioterapia Combinada , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/genética
14.
J Cardiovasc Transl Res ; 11(6): 459-469, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30302742

RESUMO

LncRNA microarray analysis was applied to investigate the exercise effect on the global differential expressions of lncRNA and mRNA in aorta endothelium in insulin resistance. Twenty-four male C57BL/6 J mice were randomly divided into three groups: control group (n = 8), high-fat diet group (n = 8), and high-fat diet plus exercise training group (n = 8). An lncRNA microarray analysis was applied to investigate the global differential expressions of lncRNA and mRNA in aorta endothelium among three groups and the results were further verified by qPCR. Hypergeometric distribution analysis was applied to reveal the possible signaling. Exercise might alleviate the vascular injury of IR via FR030200-Col3A1, FR402720-Rnd1, and FR030200/FR402720-Rnd3 signalings in cytoskeletal rearrangement pathway; E2F1-FR030200/FR402720-Nnat and FR030200/ FR402720-Fam46a signalings in anti-inflammation pathway. This study identified a panel of dysregulated lncRNAs and mRNAs that might serve as potential biomarkers relevant to the vascular injury in insulin resistance induced by high-fat diet.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Terapia por Exercício/métodos , Resistência à Insulina , Condicionamento Físico Animal/métodos , RNA Longo não Codificante/metabolismo , Animais , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Resistência à Insulina/genética , Masculino , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Fatores de Tempo , Transcriptoma
15.
Arterioscler Thromb Vasc Biol ; 38(10): 2382-2395, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354214

RESUMO

Objective- Vascular calcification is a major risk factor for rupture of atherosclerotic plaques. High expression of BMP2 (bone morphogenetic protein 2) in lesions suggests its importance in vascular calcification during atherosclerosis. Teniposide is a Topo II (DNA topoisomerase II) inhibitor and is used for cancer treatment. Previously, we reported that teniposide activated macrophage ABCA1 (ATP-binding cassette transporter A1) expression and free cholesterol efflux indicating Topo II inhibitors may demonstrate antiatherogenic properties. Herein, we investigated the effects of teniposide on the development of atherosclerosis and vascular calcification in apoE-/- (apoE deficient) mice. Approach and Results- apoE-/- mice were fed high-fat diet containing teniposide for 16 weeks, or prefed high-fat diet for 12 weeks followed by high-fat diet containing teniposide for 4 weeks. Atherosclerosis and vascular calcification were determined. Human aortic smooth muscle cells were used to determine the mechanisms for teniposide-inhibited vascular calcification. Teniposide reduced atherosclerotic lesions. It also substantially reduced vascular calcification without affecting bone structure. Mechanistically, teniposide reduced vascular calcification by inactivating BMP2/(pi-Smad1/5/8 [mothers against decapentaplegic homolog 1, 5, and 8])/RUNX2 (runt-related transcription factor 2) axis in a p53-dependent manner. Furthermore, activated miR-203-3p by teniposide functioned as a link between activated p53 expression and inhibited BMP2 expression in inhibition of calcification. Conclusions- Our study demonstrates that teniposide reduces vascular calcification by regulating p53-(miR-203-3p)-BMP2 signaling pathway, which contributes to the antiatherogenic properties of Topo II inhibitors.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Teniposídeo/farmacologia , Inibidores da Topoisomerase II/farmacologia , Calcificação Vascular/prevenção & controle , Regiões 3' não Traduzidas , Fosfatase Alcalina/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Calcificação Vascular/enzimologia , Calcificação Vascular/genética , Calcificação Vascular/patologia
16.
Arterioscler Thromb Vasc Biol ; 38(11): 2576-2589, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354239

RESUMO

Objective- ACAT1 (Acyl-CoA cholesterol acyltransferase 1) esterifies cellular free cholesterol, thereby converting macrophages to cholesteryl ester-laden foam cells in atherosclerotic lesions and cutaneous xanthoma. Paradoxically, however, loss of ACAT1 in bone marrow causes the aggravation of atherosclerosis and the development of severe cutaneous xanthoma in hyperlipidemic mice. Recently, it has been reported that cholesterol crystals activate NLRP3 (NACHT, LRR [leucine-rich repeats], and PYD [pyrin domain] domain-containing protein 3) inflammasomes, thereby contributing to the development of atherosclerosis. The present study aimed to clarify the role of NLRP3 inflammasomes in the worsening of atherosclerosis and cutaneous xanthoma induced by ACAT1 deficiency. Approach and Results- Ldlr-null mice were transplanted with bone marrow from WT (wild type) mice and mice lacking ACAT1, NLRP3, or both. After the 4 types of mice were fed high-cholesterol diets, we compared their atherosclerosis and skin lesions. The mice transplanted with Acat1-null bone marrow developed severe cutaneous xanthoma, which was filled with numerous macrophages and cholesterol clefts and had markedly increased expression of inflammatory cytokines, and increased atherosclerosis. Loss of NLRP3 completely reversed the cutaneous xanthoma, whereas it improved the atherosclerosis only partially. Acat1-null peritoneal macrophages showed enhanced expression of CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein) and TNF-α (tumor necrosis factor-α) but no evidence of inflammasome activation, after treatment with acetylated LDL (low-density lipoprotein). Conclusions- Elimination of ACAT1 in bone marrow-derived cells aggravates cutaneous xanthoma and atherosclerosis. The development of cutaneous xanthoma is induced mainly via the NLRP3 inflammasome activation.


Assuntos
Acetil-CoA C-Acetiltransferase/metabolismo , Doenças da Aorta/enzimologia , Aterosclerose/enzimologia , Medula Óssea/enzimologia , Inflamassomos/metabolismo , Macrófagos Peritoneais/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica , Dermatopatias/enzimologia , Xantomatose/enzimologia , Acetil-CoA C-Acetiltransferase/deficiência , Acetil-CoA C-Acetiltransferase/genética , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Medula Óssea/patologia , Transplante de Medula Óssea , Células Cultivadas , Colesterol na Dieta , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Macrófagos Peritoneais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fenótipo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Dermatopatias/genética , Dermatopatias/patologia , Dermatopatias/prevenção & controle , Xantomatose/genética , Xantomatose/patologia , Xantomatose/prevenção & controle
17.
Arterioscler Thromb Vasc Biol ; 38(11): 2562-2575, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354245

RESUMO

Objective- Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored. Approach and Results- First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce N-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability. N-acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE-/-) mice during atherogenesis. N-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE-/- mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties. Conclusions- The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Etanolaminas/farmacologia , Macrófagos/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Fagocitose/efeitos dos fármacos , Placa Aterosclerótica , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fenótipo , Fosfolipase D/metabolismo , Ratos , Receptores de Canabinoides/genética , Receptores de Canabinoides/metabolismo , Fatores de Tempo , c-Mer Tirosina Quinase/metabolismo
18.
Arterioscler Thromb Vasc Biol ; 38(11): 2590-2600, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354246

RESUMO

Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m- /m-) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane-associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.


Assuntos
Aorta/enzimologia , Doenças da Aorta/enzimologia , Aterosclerose/enzimologia , Movimento Celular , Hidroximetilglutaril-CoA Redutases/metabolismo , Macrófagos Peritoneais/enzimologia , Monócitos/enzimologia , Transferência Adotiva , Animais , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Hidroximetilglutaril-CoA Redutases/genética , Lipídeos/sangue , Macrófagos Peritoneais/patologia , Macrófagos Peritoneais/transplante , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fenótipo , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais
19.
Nutrients ; 10(10)2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30326655

RESUMO

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv®, an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv® is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of fruit and vegetables commonly consumed within the Mediterranean diet. A total of 21 Golden Syrian hamsters were divided into three groups. The standard group (STD) was fed a normolipidemic diet for 12 weeks, while the control group (CTRL) and Oleactiv® goup (OLE) were fed a high-fat diet. After sacrifice, the aortic fatty streak area (AFSA), plasmatic total cholesterol (TC), high-density lipoproteins (HDL-C), non-HDL-C and triglycerides (TG), were assessed. The cholesterol efflux capacity (CEC) of hamster plasma was quantified using a radiolabeled technique in murine macrophages J774. OLE administration induced a significant reduction of AFSA (-69%, p < 0.0001). Hamsters of the OLE group showed a significant decrease of both non-HDL-C (-173 mmol/L, p < 0.05) and TG (-154 mmol/L, p < 0.05). Interestingly, OLE induced a significant increase of total CEC (+17,33%, p < 0,05). Oleactiv® supplementation prevented atheroma development and had positive effects on the lipid profile of hypercholesterolemic hamsters. The increased CEC underlines the anti-atherosclerotic mechanism at the root of the atheroma reduction observed.


Assuntos
Anticolesterolemiantes/farmacologia , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Colesterol/sangue , Suplementos Nutricionais , Hipercolesterolemia/tratamento farmacológico , Polifenóis/farmacologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Linhagem Celular , HDL-Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Mesocricetus , Camundongos , Placa Aterosclerótica , Triglicerídeos/sangue
20.
Atherosclerosis ; 277: 28-33, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30170221

RESUMO

BACKGROUND AND AIMS: Diets enriched with tree nuts have been demonstrated to reduce the risk of atherosclerosis-related cardiovascular events. Abdominal aortic aneurysm (AAA) shares common risk factors with atherosclerosis and AAA patients commonly have atherosclerosis related cardiovascular events. AAA has some distinct pathological and clinical characteristics to those of atherosclerosis. No previous study has examined the effect of a diet enriched with tree nuts on experimental or clinical AAA. This study investigated the effect of a diet enriched with tree nuts on the development and severity of AAA within an experimental rodent model. METHODS: Male apolipoprotein E deficient mice were allocated to a diet enriched with tree nuts or control diet for 56 days (n = 17 per group). After 28 days, all mice were infused with angiotensin II whilst being maintained on their respective diets. The primary outcome was AAA severity assessed by the supra-renal aortic diameter, measured by ultrasound and ex vivo morphometric analysis. The severity of atherosclerosis was assessed by computer-aided analysis of Sudan IV stained aortic arches and sections of brachiocephalic arteries prepared with Van Gieson's stain. RESULTS: The diet enriched with tree nuts did not influence aortic diameter or aortic rupture incidence. Mice receiving the diet enriched with tree nuts had significantly less atherosclerosis within the brachiocephalic artery (p = 0.033) but not in the aortic arch. CONCLUSIONS: This experimental study suggests that a diet enriched with tree nuts does not reduce the severity of AAA, but does reduce the severity of atherosclerosis within the brachiocephalic artery. The study was not powered to identify a moderate effect of the diet on the primary outcome and therefore this cannot be excluded.


Assuntos
Angiotensina II , Ração Animal , Aneurisma da Aorta Abdominal/prevenção & controle , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Ácidos Graxos Ômega-3/administração & dosagem , Nozes , Polifenóis/administração & dosagem , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Tronco Braquiocefálico/metabolismo , Tronco Braquiocefálico/patologia , Dilatação Patológica , Modelos Animais de Doenças , Masculino , Camundongos Knockout para ApoE , Valor Nutritivo , Placa Aterosclerótica , Índice de Gravidade de Doença , Fatores de Tempo
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