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1.
Int Heart J ; 61(2): 364-372, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32132319

RESUMO

Atherosclerosis is a chronic inflammatory disease with multiple characteristic facets, including vascular inflammation, endothelial dysfunction, plaque development, impaired blood flow, and cholesterol deposition through dyslipidemia. Toll-like receptors (TLRs) of the innate immune system have been closely linked to the development of atherosclerotic lesions. TLR7 recognizes viral or endogenous single-stranded RNA, which is released during vascular apoptosis and necrosis. The role of TLR7 in vascular disease remains controversial, and therefore, we sought to investigate the effects of TLR7 stimulation in mice.Intravenous injection of a ligand for TLR7 (R848) induced a significant pro-inflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid artery, as measured by Evan's blue staining, and increased numbers of circulating endothelial microparticles (EMPs) and circulating Sca1/Flk1 positive cells as a marker for increased endothelial damage. Chronic subcutaneous stimulation of TLR7 in apolipoprotein E-deficient (ApoE-/-) mice increased aortic production of reactive oxygen species (ROS), the number of circulating EMPs, and most importantly, augmented the formation of atherosclerotic plaque when compared with vehicle-treated animals.Systemic stimulation of TLR7 leads to impaired reendothelialization upon acute vascular injury and is associated with the production of pro-inflammatory cytokines and increased levels of circulating EMPs and Sca1/Flk1 positive cells. Importantly, ApoE-/- mice chronically treated with R848 displayed increased atherosclerotic plaque development and elevated levels of ROS in the aortic tissue. In addition, TLR7-activation-induced apoptosis and impaired migration in human coronary artery endothelial cells and showed significant upregulation of the signaling cascade of IL-1 receptor-associated kinase (IRAK) 2 and IRAK4. Our data highlight the importance of fully understanding the pathomechanisms involved in atherogenesis, and further studies are necessary to identify the ligand-specific effects of TLR7 for possible therapeutic targeting.


Assuntos
Aterosclerose/etiologia , Glicoproteínas de Membrana/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Apoptose , Aterosclerose/metabolismo , Movimento Celular , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Citocinas/metabolismo , Células Endoteliais/fisiologia , Humanos , Imidazóis , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Camundongos Knockout para ApoE
3.
PLoS One ; 15(2): e0228415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084149

RESUMO

Ribose-cysteine is a synthetic compound designed to increase glutathione (GSH) synthesis. Low levels of GSH and the GSH-dependent enzyme, glutathione peroxidase (GPx), is associated with cardiovascular disease (CVD) in both mice and humans. Here we investigate the effect of ribose-cysteine on GSH, GPx, oxidised lipids and atherosclerosis development in apolipoprotein E-deficient (apoE-/-) mice. Female 12-week old apoE-/- mice (n = 15) were treated with 4-5 mg/day ribose-cysteine in drinking water for 8 weeks or left untreated. Blood and livers were assessed for GSH, GPx activity and 8-isoprostanes. Plasma alanine transferase (ALT) and lipid levels were measured. Aortae were quantified for atherosclerotic lesion area in the aortic sinus and brachiocephalic arch and 8-isoprostanes measured. Ribose-cysteine treatment significantly reduced ALT levels (p<0.0005) in the apoE-/- mice. Treatment promoted a significant increase in GSH concentrations in the liver (p<0.05) and significantly increased GPx activity in the liver and erythrocytes of apoE-/-mice (p<0.005). The level of 8-isoprostanes were significantly reduced in the livers and arteries of apoE-/- mice (p<0.05 and p<0.0005, respectively). Ribose-cysteine treatment showed a significant decrease in total and low density lipoprotein (LDL) cholesterol (p<0.05) with no effect on other plasma lipids with the LDL reduction likely through upregulation of scavenger receptor-B1 (SR-B1). Ribose-cysteine treatment significantly reduced atherosclerotic lesion area by >50% in both the aortic sinus and brachiocephalic branch (p<0.05). Ribose-cysteine promotes a significant GSH-based antioxidant effect in multiple tissues as well as an LDL-lowering response. These effects are accompanied by a marked reduction in atherosclerosis suggesting that ribose-cysteine might increase protection against CVD.


Assuntos
Antioxidantes/administração & dosagem , Apolipoproteínas E/deficiência , Aterosclerose/prevenção & controle , Cisteína/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ribose/administração & dosagem , Animais , Antioxidantes/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Cisteína/metabolismo , Feminino , Lipídeos/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Oxirredução , Substâncias Protetoras/metabolismo , Ribose/metabolismo
4.
Nat Commun ; 11(1): 214, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924781

RESUMO

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions.


Assuntos
Aterosclerose/metabolismo , Endotélio/metabolismo , MicroRNAs/metabolismo , Neutrófilos/metabolismo , Animais , Aterosclerose/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais , Endotélio/patologia , Regulação da Expressão Gênica , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout para ApoE , MicroRNAs/genética , NF-kappa B/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia
5.
BMC Cardiovasc Disord ; 20(1): 32, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992206

RESUMO

BACKGROUND: The gut microbiome plays an important role in various cardiovascular diseases, such as atherosclerosis and hypertension, which are associated with abdominal aortic aneurysms (AAAs). METHODS: Here, we used 16S rRNA sequencing to explore gut microbiota in C57BL ApoE-/- mice with AAAs. A mouse model of abdominal aortic aneurysms was induced with angiotensin II (Ang II) (1000 ng/min per kg). On day 28 after the operation, fecal samples were collected and stored at - 80 °C until DNA extraction. We determined the relative abundances of bacterial taxonomic groups using 16S rRNA amplicon metabarcoding, and sequences were analyzed using a combination of mother software and UPARSE. RESULTS: We found that the gut microbiome was different between control and AAA mice. The results of correlation analysis between AAA diameter and the gut microbiome as well as LEfSe of the genera Akkermansia, Odoribacter, Helicobacter and Ruminococcus might be important in the progression of AAAs. CONCLUSIONS: AAA mice is subjected to gut microbial dysbiosis, and gut microbiota might be a potential target for further investigation.


Assuntos
Aneurisma da Aorta Abdominal/microbiologia , Bactérias/crescimento & desenvolvimento , Microbioma Gastrointestinal , Intestinos/microbiologia , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Bactérias/genética , Bactérias/isolamento & purificação , Modelos Animais de Doenças , Disbiose , Fezes/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Ribotipagem
6.
Am J Pathol ; 190(3): 563-576, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31945314

RESUMO

Hyperlipidemia impacts on various diseases, such as atherosclerosis, hypertension, and diabetes mellitus. However, its influence, if any, on ocular tissues is largely unknown. Herein, we developed hyperlipidemic murine models by feeding 4-week-old male wild-type mice with a high-fat diet and apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet or standard diet to investigate the corneal endothelial change under hyperlipidemic conditions. Oil Red O staining showed an accumulation of lipid droplets in corneal endothelial cells (CECs) of hyperlipidemic mice. Other manifestations included a reduced cell density and distorted cell morphology, a disruption of the endothelial cell tight junctions and adhesion junctions, a reduced number of surface microvilli, down-regulation of Na+-K+-ATPase expression and function, activation of oxidative stress, changes in mitochondrial ultrastructure, and increased apoptosis. CEC recovery after injury, moreover, was diminished in hyperlipidemic mice; and high palmitate levels were found in the aqueous humor. In vitro hyperlipemia model, moreover, was found to be associated with dose-dependent CEC cytotoxicity, altered cell morphology, reduced pump function, and an induction of oxidative stress, leading to functional and pathologic changes in the corneal endothelium.


Assuntos
Apolipoproteínas E/genética , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/complicações , Estresse Oxidativo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Apoptose , Sobrevivência Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epitélio Posterior/metabolismo , Epitélio Posterior/patologia , Hiperlipidemias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Mitocôndrias/ultraestrutura , Palmitatos/toxicidade , ATPase Trocadora de Sódio-Potássio/genética , Junções Íntimas/metabolismo , Junções Íntimas/patologia
7.
J Ethnopharmacol ; 246: 112207, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476440

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liuwei Dihuang (LWDH) is a classic prescription that has been used as a traditional medicinal formula for more than 1000 years in China. In clinical, LWDF is used for treating functional decline associated with senile disease and menopausal syndrome. Studies have demonstrated that LWDH could significantly improve estrogen level and ER expression, and suspend the process of atherosclerosis. However, the under mechanism of how LWDH suppressing VSMCs phenotypic conversion and proliferation through ER is still unknown. AIM OF THE STUDY: This study was to reveal the under mechanism of how LWDH inhibits the phenotypic conversion of VSMCs. MATERIALS AND METHODS: 24 ApoE-/- mice were divided into 4 groups: sham group, model group, E2 group, and LWDH group, and 6 C57BN/L6 mice were used as control group. The primary VSMCs were divided into control group, model group, E2 group, LWDH group, LWDH + MPP group, and LWDH + PHTPP group with or without control siRNA, ERα siRNA, ERß siRNA, and myocardin siRNA. Oil red staining was used to evaluate the lipid deposition in the cardiac aorta. Serum chemistry analysis to test serum TG, TC, LDL, and HDL. Immunofluorescence staining was used to test α-SMA, osteopontin and F-actin. Immunohistochemical staining was performed to check out the myocardin in the cardiac aorta. The mRNA levels of α-SMA, osteopontin, ERα, ERß, SRC3 and myocardin were detected by Real Time-PCR, and the protein expression levels of them were detected by Western blotting. Co-immunoprecipitation was proceed to test the interaction between ERα and SRC3 and SRC3 and myocardin. Flow cytometry was used to check out the cell cycle. Wound healing assay and Transwell were managed to evaluate the migration capacity of VSMCs. RESULTS: In vivo administration of LWDH suppressed AS symptoms, decreases phenotypic marker of vascular endothelial cell, and increases phenotypic marker of VSMC in ovariectomized ApoE-/- female mice. Moreover, LWDH significantly increased the mRNA and protein expression levels of ERα, ERß, SRC3 and myocardin in the cardiac aorta of ovariectomized ApoE-/- female mice. In vitro, LWDH altered cell cycle and reduced the elevated cyclinD protein expression migration capacity and in the model VSMCs. In addition, LWDH inhibited phenotypic conversion and promoted the expression of ER, SRC3, and myocardin of the primary VSMC phenotypic conversion model. Inhibition of ERα almost completely eliminated the impacts of LWDH on α- SMA and osteopontin. Furthermore, LWDH promoted the interaction between ERα and SRC3 and up-regulated the co-activation of SRC3 and myocardin. CONCLUSIONS: LWDH could inhibit the phenotypic conversion of VSMCs in vitro and in vivo by increasing the activity of myocardin through up-regulating the expression of ERα and promoting the interaction between ERα and SRC3. Our research reveals the under mechanism of how LWDH inhibits the phenotypic conversion of VSMCs.


Assuntos
Aterosclerose/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Aorta/metabolismo , Cápsulas , Células Cultivadas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Menopausa/genética , Menopausa/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares/genética , Osteopontina/genética , Osteopontina/metabolismo , Fenótipo , Ratos Sprague-Dawley , Transativadores/genética , Regulação para Cima/efeitos dos fármacos
8.
J Ethnopharmacol ; 247: 112232, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31606534

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-Tetrahydroxy-stilbene-2-O-ß-D-glucoside (TSG) is the main active component of Polygoni Multiflori Radix, a root of the homonymous plant widely used in traditional Chinese medicine. TSG has protective effects on the liver, reduces cholesterol and possesses anti-oxidant, anti-tumor, and anti-atherosclerotic properties. However, the pharmacological effects and mechanisms of action of Polygonum multiflorum on atherosclerosis (AS) have not been studied yet. PURPOSE: The aim of this research was to study the effects of Polygoni Multiflori Radix Praeparata (PMRP) and its major active chemical constituent TSG on AS in ApoE-deficient (ApoE-/-) mice fed with high fat diets to provide a scientific basis in the use of PMRP and TSG against cardiovascular diseases. METHODS: High fat diet induced AS in ApoE-/- mice were treated with PMRP, TSG (low and high doses), and simvastatin (SIM) for 8 weeks. At the end of the treatment, mouse serum lipid levels, triglycerides (TG), and total cholesterol (TC) were measured by an oxidase method (other indicators were determined by ELISA), while the content in oxidized low density lipoprotein (ox-LDL) and the expression of inflammatory factors such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1) in the serum and aortic samples were measured by ELISA. Atherosclerotic plaque morphology was evaluated by oil red O in thoracic aorta. In addition, 16S rDNA-V4 hypervariable region genome sequence of all microbes in the fecal sample from each group was analyzed to evaluate potential structure changes in the gut microbiota after treatment with PMRP and TSG. RESULTS: TSG markedly inhibited AS plaque formation in ApoE-/- mice. Furthermore, PMRP and TSG improved lipid accumulation by reducing TG and ox-LDL levels. TSG inhibited inflammation by the down-regulation of IL-6, TNF-α, VCAM-1 and MCP-1 expression in serum, and PMRP inhibited inflammation by reducing VCAM-1, ICAM-1 and CCRA expression in aortic tissue. In addition, TSG reduced or prevented AS by the regulation of the composition of the overall gut microbiota, such as Firmicutes, Bacteroidetes, Tenericutes, Proteobacteria phyla, Akkermensia genera and Helicobacter pylori. CONCLUSION: PMRP and TSG improved lipid accumulation and inflammation, and regulated the intestinal microbial imbalance in ApoE-/- mice. TSG exerted a preventive effect in the development and progression of AS.


Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Polygonum/química , Estilbenos/farmacologia , Administração Oral , Animais , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/imunologia , Glucosídeos/uso terapêutico , Humanos , Inflamação/sangue , Inflamação/etiologia , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Lipoproteínas LDL/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Estilbenos/uso terapêutico , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
9.
J Pharmacol Sci ; 142(1): 9-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771811

RESUMO

Varenicline is a widely used and effective drug for smoking cessation. We previously reported that varenicline aggravates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. However, it remains unknown whether varenicline affects cardiovascular events in patients with nicotine addiction. Here, we examined the effect of varenicline on atherosclerotic plaque formation in nicotine-pretreated ApoE KO mice and oxidized low-density lipoprotein (oxLDL) uptake in nicotine-treated peritoneal macrophages. Varenicline caused significant progression of plaque formation in the whole aorta and aortic root and further accelerated the increased formation of a macrophage-rich plaque area in the aortic root in nicotine-pretreated ApoE KO mice. Varenicline (10 µM) enhanced oxLDL uptake in peritoneal macrophages. Furthermore, this treatment significantly further lowered the decreased protein levels of ATP-binding cassette (ABC) transporter without affecting the expression of scavenger receptors LOX-1 and CD36 in RAW264.7 cells treated with 100 nM nicotine. Varenicline enhanced nicotine-induced oxLDL uptake in macrophages through decreased expression of cholesterol efflux transporters ABCA1 and ABCG1 and thereby progressed atherosclerotic plaque formation. Taken together, we tentatively conclude that nicotine exposure before and/or during varenicline treatment can aggravate varenicline-increased atherosclerotic plaque formation and progression. Therefore, this enhanced risk requires special consideration when prescribing varenicline to smoker patients.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Macrófagos/metabolismo , Nicotina/farmacologia , Placa Aterosclerótica/etiologia , Vareniclina/toxicidade , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Nicotina/agonistas , Células RAW 264.7 , Agentes de Cessação do Hábito de Fumar/toxicidade
10.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 9-17, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31867609

RESUMO

Increased glycolysis is involved in the proliferation and migration of vascular smooth muscle cells (VSMCs). Pyruvate kinase isoform M2 (PKM2), a key rate-limiting enzyme in glycolysis, accelerates the proliferation and migration of tumor cells. Although the intracellular mechanisms associated with oxidized low-density lipoprotein (oxLDL)-stimulated VSMC proliferation and migration have been extensively explored, it is still unclear whether oxLDL promotes the proliferation and migration of VSMCs by enhancing PKM2-dependent glycolysis. In the present study, we detected PKM2 expression and pyruvate kinase activity in oxLDL-treated VSMCs and explored the regulation of PKM2 in oxLDL-treated VSMCs and apoE-/- mice. The results showed that PKM2 expression in VSMCs was higher in the intima than in the media in plaques from atherosclerotic rabbits. Moreover, PKM2 level in VSMCs was increased during atherosclerosis progression in apoE-/- mice. Both PKM2 expression and pyruvate kinase activity were found to be upregulated by oxLDL stimulation in VSMCs. Shikonin (SKN), a specific inhibitor of PKM2, was found to inhibit the oxLDL-induced proliferation and migration in VSMCs, in addition to delaying the atherosclerosis progression in apoE-/- mice. More importantly, oxLDL increased glucose uptake, ATP and lactate production, and the extracellular acidification rate in VSMCs, which could be reversed by SKN. Meanwhile, oxygen consumption rate was unchanged after oxLDL stimulation, suggesting that glycolysis is the main contributor to the energy supply in oxLDL-treated VSMCs. Our results suggest that oxLDL induces VSMC proliferation and migration by upregulating PKM2-dependent glycolysis, thereby contributing to the atherosclerosis progression. Thus, targeting PKM2-dependent glycolysis might provide a novel therapeutic approach for the treatment of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Proteínas de Transporte/metabolismo , Movimento Celular , Proliferação de Células , Glicólise/genética , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Piruvato Quinase/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout para ApoE , Naftoquinonas/farmacologia , Piruvato Quinase/antagonistas & inibidores , Piruvato Quinase/genética , Coelhos , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/genética
11.
Environ Health Perspect ; 127(11): 117003, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31724879

RESUMO

BACKGROUND: Atherosclerotic cardiovascular disease has become the leading cause of death worldwide, and environmental pollutants are increasingly recognized as risk factors for atherosclerosis. Liver X receptors (LXRs) play a central role in atherosclerosis; however, LXR activity of organic pollutants and associated potential risk of atherosclerosis have not yet been characterized. OBJECTIVES: This study aimed to explore whether LXR-antagonistic chemicals are present in indoor house dust and, if so, to characterize this activity in relation to changes in macrophages in vitro and cardiovascular disease indicators in vivo in an atherosclerosis ApoE-/- mouse model. METHODS: We used a His-LXRα-pull-down assay and a nontarget high-resolution mass spectrometry method to screen house dust collected from Chinese homes for LXRα- and LXRß-antagonist activity. A chemical identified in this manner was assessed for its ability to induce cholesterol efflux and foam cell formation in RAW264.7 macrophages, to down-regulate the expression of two LXR-dependent genes, ABCA1 and ABCG1, and finally to induce atherosclerotic lesions in vivo using an ApoE-/- mouse model. RESULTS: We identified the flame retardants triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) in house dust samples and demonstrated their ability to antagonize LXRs. The potency of TPHP was similar to that of the LXR-antagonist SR9238. TPHP could also inhibit cholesterol efflux and promote foam cell formation in RAW264.7 macrophages and mouse peritoneal macrophages and significantly promoted atherosclerotic lesion formation in the ApoE-/- mouse model. CONCLUSIONS: We found LXR-antagonist chemicals in environmental samples of indoor dust from Chinese homes. One of the chemicals, TPHP, was able to promote the development of atherosclerotic lesions in the ApoE-/- mouse model. These results highlight the need to assess the LXR-antagonist activities of pollutants in future environmental management programs. https://doi.org/10.1289/EHP5039.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Aterosclerose/fisiopatologia , Poeira/análise , Animais , Aterosclerose/induzido quimicamente , China , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Células RAW 264.7
12.
Vasc Health Risk Manag ; 15: 309-316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692533

RESUMO

Experimentally induced injury triggers up-regulation and mobilization of stem cells in Apoe -/- mice that causes accelerated atherosclerosis. Abca1 -/- Abcg1-/- mice have chronic activation of stem cell up-regulation/mobilization and accelerated atherosclerosis. In addition, the Abca1 -/- Abcg1-/- mice have elevation of serum cytokines G-CSF, IL-17 and IL-23, each necessary for stem cell mobilization. IL-17 and IL-23 are elevated in two human illnesses that have cardiovascular (CV) risk independent of traditional risk factors-SLE and psoriasis. Serum G-CSF, which can be elevated in liver disease, predicts major adverse cardiovascular events in humans. These serum cytokine elevations suggest activation of the stem cell mobilization mechanism in humans that results, as in mice, in accelerated atherosclerosis. Efforts to reduce CV disease in these patient populations should include mitigation of the diseases that trigger stem cell mobilization. Since activation of the stem cell up-regulation/mobilization mechanism appears to accelerate human atherosclerosis, use of stem cells as therapy for arterial occlusive disease should distinguish between direct administration of stem cells and activation of the stem cell up-regulation/mobilization mechanism.


Assuntos
Doenças Cardiovasculares/patologia , Movimento Celular , Hepatopatias/patologia , Psoríase/patologia , Células-Tronco/patologia , Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mediadores da Inflamação/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/terapia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos Knockout para ApoE , Fenótipo , Prognóstico , Psoríase/genética , Psoríase/metabolismo , Psoríase/terapia , Fatores de Risco , Células-Tronco/metabolismo
13.
Life Sci ; 237: 116943, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31604109

RESUMO

AIMS: The purpose of this study was to investigate the therapeutic effect of artemisinin (ART) on atherosclerosis and explore the molecular mechanisms involved by RNA sequencing (RNA-Seq). MAIN METHODS: Eight-week-old male ApoE-/- mice were treated with ART for eight weeks. Atherosclerotic lesion sizes were determined by Oil Red O staining, and RNA-Seq was used to detect the profile of differentially expressed genes following the administration of ART. The expressions of contractile phenotypic markers were detected by western blot and qRT-PCR, and the ability of the MOVAS cells to migrate and proliferate were assessed using the wound healing and CCK8 assays. KEY FINDINGS: Artemisinin treatment significantly reduced plaque area in the ApoE-/- mice and increased the expression of contractile phenotypic markers. RNA-Seq of aorta tissue revealed a distinct change in gene expression patterns after the mice were treated with ART. Our bioinformatics analysis demonstrated that the most prominently enriched pathway was a set of genes involved in vascular smooth muscle contractile function. Using an in vitro cell model, we demonstrated that ART could effectively reverse PDGF-activated MOVAS migration and proliferation, and elevate the level of proteins involved in the contractile phenotype. SIGNIFICANCE: We provide in vivo and in vitro evidence supporting a role for ART in the suppression of atherosclerosis, partly through the inhibition of vascular smooth muscle cell phenotype switching to a de-differentiated phenotype. These data further advances our understanding for a potential role for ART and suggests that ART is an excellent candidate for the treatment of atherosclerosis.


Assuntos
Antimaláricos/farmacologia , Apolipoproteínas E/fisiologia , Artemisininas/farmacologia , Aterosclerose/prevenção & controle , Proliferação de Células , Modelos Animais de Doenças , Músculo Liso Vascular/citologia , Animais , Aterosclerose/etiologia , Aterosclerose/patologia , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fenótipo , Transdução de Sinais
14.
Life Sci ; 237: 116896, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605707

RESUMO

AIMS: Population-based studies have shown that exercise has anti-atherosclerotic effects, but the mechanisms underlying this cardiac protection are poorly understood. The aim of this study was to investigate if the anti-atherosclerotic effects of exercise are associated with changes in neuropeptide Y (NPY) expression in apolipoprotein E-deficient (ApoE-/-) mice. MAIN METHODS: Thirty-one male ApoE-/- mice were randomly divided into regular exercise (5 days/week), occasional exercise (1-2 days/week), and sedentary groups. After 8 weeks, atherosclerotic burden and plaque stability were measured by histological and morphological analysis. Quantitative real-time PCR and immunohistochemistry were used to measure the expression of NPY and its receptors in the aorta. KEY FINDINGS: Eight weeks of occasional exercise was equally effective as regular exercise at preventing atherosclerotic plaque formation and enhancing atherosclerotic plaque stability. This was shown by increased plaque collagen and smooth muscle cell content and decreased plaque lipid and macrophage content. The expression of NPY and its receptors in the vasculature was decreased in the regular exercise and occasional exercise groups, and this expression was significantly correlated with the progress of atherosclerosis. Moreover, exercise may reduce the activity of macrophages by down-regulating the expression of NPY Y1 receptors, thereby reducing the release of inflammatory cytokines. SIGNIFICANCE: These results suggest that exercise training can attenuate plaque burden and enhance atherosclerotic plaque stability. The anti-atherosclerotic effect of exercise appears to be, at least in part, dependent on down-regulation of the expression of NPY and its receptors (especially Y1 receptors) in the aorta.


Assuntos
Apolipoproteínas E/fisiologia , Aterosclerose/prevenção & controle , Regulação da Expressão Gênica , Inflamação/prevenção & controle , Neuropeptídeo Y/metabolismo , Condicionamento Físico Animal , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neuropeptídeo Y/genética
16.
J Vasc Res ; 56(5): 241-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536996

RESUMO

PURPOSE: Atherosclerosis in the carotid arteries is a common cause of ischemic stroke. We examined atherogenesis in the left carotid artery with and without interrupted blood flow of C57BL/6 (B6) and C3H-Apoe-deficient (Apoe-/-) mouse strains. METHODS: Blood flow was interrupted by ligating the common carotid artery near its bifurcation in one group of mice and another group was not interrupted. RESULTS: Without interference with blood flow, C3H-Apoe-/- mice developed no atherosclerosis in the carotid artery, while B6-Apoe-/- mice formed advanced atherosclerotic lesions (98,019 ± 10,594 µm2/section) after 12 weeks of a Western diet. When blood flow was interrupted by ligating the common carotid artery near its bifurcation, C3H-Apoe-/- mice showed fatty streak lesions 2 weeks after ligation, and by 4 weeks fibrous lesions had formed, although they were smaller than in B6-Apoe-/- mice. Neutrophil adhesion to endothelium and infiltration in lesions was observed in ligated arteries of both strains. Treatment of B6-Apoe-/- mice with antibody against neutrophils had little effect on lesion size. CONCLUSIONS: These findings demonstrate the dramatic influences of genetic backgrounds and blood flow on atherogenesis in the carotid artery of hyperlipidemic mice.


Assuntos
Doenças das Artérias Carótidas/etiologia , Artéria Carótida Primitiva/fisiopatologia , Hiperlipidemias/complicações , Placa Aterosclerótica , Animais , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/cirurgia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Hiperlipidemias/genética , Ligadura , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fluxo Sanguíneo Regional , Especificidade da Espécie , Fatores de Tempo
17.
Diab Vasc Dis Res ; 16(6): 562-576, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31530180

RESUMO

Diabetes contributes directly to the development of cardiovascular aortic valve disease. There is currently no drug therapy available for a dysfunctional valve and this urges the need for additional research to identify distinctive mechanisms of cardiovascular aortic valve disease evolution. The aim of this study was to evaluate changes of valvular aortic lesions induced in a hyperlipemic ApoE-/- mouse model by early type 1 diabetes onset (at 4 and 7 days after streptozotocin induction). The haemodynamic valve parameters were evaluated by echography and blood samples and aortic valves were collected. Plasma parameters were measured, and inflammatory, remodelling and osteogenic markers were evaluated in the aortic valves. Next, correlations between all parameters were determined. The results showed early aortic valve dysfunction detected by echography after 1 week of diabetes; lesions were found in the aortic root. Moreover, increased expression of cell adhesion molecules, extracellular matrix remodelling and osteogenic markers were detected in hyperlipemic ApoE-/- diabetic mice. Significant correlations were found between tissue valve biomarkers and plasmatic and haemodynamic parameters. Our study may help to understand the mechanisms of aortic valve disease in the diabetic milieu in order to discover and validate new biomarkers of cardiovascular aortic valve disease in diabetes and reveal new possible targets for nanobiotherapies.


Assuntos
Valva Aórtica , Aterosclerose/complicações , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Doenças das Valvas Cardíacas/etiologia , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Glicemia/metabolismo , Moléculas de Adesão Celular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Hemoglobina A Glicada/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/fisiopatologia , Hemodinâmica , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Masculino , Camundongos Knockout para ApoE , Osteogênese , Fatores de Tempo
18.
Toxicol Lett ; 316: 27-34, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513887

RESUMO

OBJECTIVE: Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5. METHODS: We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively. RESULTS: The daily average concentration of PM2.5 was 57.4 ± 25.6 µg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-ß, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group. CONCLUSION: These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Material Particulado/toxicidade , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores/sangue , LDL-Colesterol/sangue , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Predisposição Genética para Doença , Mediadores da Inflamação/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Tamanho da Partícula , Fenótipo , Placa Aterosclerótica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fatores de Tempo
19.
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
20.
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
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