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1.
Sci Rep ; 9(1): 420, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674978

RESUMO

Obesity increases the risk for cardiometabolic diseases. N-acyl phosphatidylethanolamines (NAPEs) are precursors of N-acylethanolamides, which are endogenous lipid satiety factors. Incorporating engineered bacteria expressing NAPEs into the gut microbiota retards development of diet induced obesity in wild-type mice. Because NAPEs can also exert anti-inflammatory effects, we hypothesized that administering NAPE-expressing bacteria to low-density lipoprotein receptor (Ldlr)-/- mice fed a Western diet would improve various indices of cardiometabolic disease manifested by these mice. NAPE-expressing E. coli Nissle 1917 (pNAPE-EcN), control Nissle 1917 (pEcN), or vehicle (veh) were given via drinking water to Ldlr-/- mice for 12 weeks. Compared to pEcN or veh treatment, pNAPE-EcN significantly reduced body weight and adiposity, hepatic triglycerides, fatty acid synthesis genes, and increased expression of fatty acid oxidation genes. pNAPE-EcN also significantly reduced markers for hepatic inflammation and early signs of fibrotic development. Serum cholesterol was reduced with pNAPE-EcN, but atherosclerotic lesion size showed only a non-significant trend for reduction. However, pNAPE-EcN treatment reduced lesion necrosis by 69% indicating an effect on preventing macrophage inflammatory death. Our results suggest that incorporation of NAPE expressing bacteria into the gut microbiota can potentially serve as an adjuvant therapy to retard development of cardiometabolic disease.


Assuntos
Doenças Cardiovasculares , Escherichia coli/crescimento & desenvolvimento , Microbioma Gastrointestinal , Cirrose Hepática , Fígado/metabolismo , Fosfatidiletanolaminas/biossíntese , Receptores de LDL/deficiência , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/prevenção & controle , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/microbiologia , Cirrose Hepática/prevenção & controle , Camundongos , Triglicerídeos/genética , Triglicerídeos/metabolismo
2.
Atherosclerosis ; 242(1): 56-64, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26184694

RESUMO

OBJECTIVE: Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model. METHODS: Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response. RESULTS: UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change. CONCLUSION: Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Losartan/uso terapêutico , Macrófagos/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Tiazolidinedionas/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apoptose/efeitos dos fármacos , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Citocinas/biossíntese , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Hiperlipidemias/complicações , Hiperlipidemias/genética , Inflamação , Losartan/administração & dosagem , Losartan/farmacologia , Macrófagos/classificação , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrectomia , PPAR gama/agonistas , Fenótipo , Pioglitazona , Sistema Renina-Angiotensina/efeitos dos fármacos , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologia
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