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1.
High Blood Press Cardiovasc Prev ; 27(1): 1-8, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31925708

RESUMO

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Dislipidemias/metabolismo , Endotélio Vascular/metabolismo , MicroRNAs/metabolismo , Pró-Proteína Convertase 9/metabolismo , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Biomarcadores/metabolismo , Dislipidemias/enzimologia , Dislipidemias/genética , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , MicroRNAs/genética , Placa Aterosclerótica , Transdução de Sinais
2.
Environ Health Prev Med ; 24(1): 69, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31785607

RESUMO

BACKGROUND: Even though there is bidirectional association between hypertension and atherosclerosis, atherosclerosis itself is involved in the process of endothelial repair. To clarify the association of endothelial repair with hypertension, a cross-sectional study was conducted. METHODS: We conducted a cross-sectional study of 562 elderly Japanese men aged 60-69. As gamma-glutamyl transpeptidase (γ-GTP) could act as a marker of oxidative stress that injures endothelial cell and higher levels of CD34-positive cell indicate a higher activity of endothelial repair, we therefore performed a CD34-positive level specific analysis of γ-GTP on atherosclerosis and hypertension. RESULTS: In the present study population, hypertension was independently and positively associated with atherosclerosis (multivariable odds ratio (OR) = 2.09 (1.30, 3.35)). Among participants with high CD34-positive cells, γ-GTP showed significant and positive association with atherosclerosis (OR of the log-transformed value of γ-GTP (OR) = 2.26 (1.32, 3.86)) but not with hypertension (OR = 0.77 (0.51, 1.17)). Among participants with low CD34-positive cells, even γ-GTP showed no significant association with atherosclerosis (OR = 0.92 (0.51, 1.68)), but was significantly and positively associated with hypertension (OR = 1.99 (1.27, 3.12)). CONCLUSIONS: γ-GTP revealed to have ambivalent association with hypertension and atherosclerosis. Active endothelial repair that is associated with atherosclerosis might have beneficial association with hypertension.


Assuntos
Aterosclerose/enzimologia , Hipertensão/enzimologia , gama-Glutamiltransferase/sangue , Idoso , Antígenos CD34/análise , Aterosclerose/sangue , Aterosclerose/epidemiologia , Aterosclerose/patologia , Biomarcadores/sangue , Estudos Transversais , Células Endoteliais/química , Células Endoteliais/patologia , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/patologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances
3.
BMC Neurol ; 19(1): 291, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31735164

RESUMO

BACKGROUND: Mutations of cyclooxygenase gene (COX gene) may increase the susceptibility of ischemic stroke. We investigated five variants (rs5788, rs1330344, rs3842788, rs20417, and rs689466) of two COX genes in order to explaining the association between these polymorphisms and we also investigated the association between these variants and ischemic stroke risk to determine whether gene-gene interaction between these genes increases the susceptibility of ischemic stroke or its subtypes. METHODS: A total of 1981 study subjects (1078 cases and 903 control subjects) were recruited. The interaction of multiple factors was investigated using Multifactor Dimensionality Reduction. The additive effect of single nucleotide polymorphisms on ischemic stroke or its subtypes were analyzed by multiple factor logistic regression. RESULTS: At COX-1(rs1330344), AA genotype carriers had a lower susceptibility of ischemic stroke (OR = 0.657, 95%CI = 0.437-0.988, P = 0.044), and A allele carriers had a lower susceptibility of ischemic stroke (OR = 0.812, 95%CI = 0.657-0.978, P = 0.029). At COX-1(rs3842788), AA genotype carriers had a higher susceptibility of ischemic stroke (OR = 5.203, 95% CI = 1.519-5.159, P = 0.016). At COX-2 (rs689466), AA genotype carriers had a higher susceptibility of large-artery atherosclerosis (OR = 1.404, 95% CI = 1.019-1.934, P = 0.038). COX-1(rs1330344, rs3842788) and COX-2 rs689466 interacted in SVO, but had no additive effect with ischemic stroke and other subtypes. CONCLUSIONS: At rs1330344, AA genotype may reduce the susceptibility of ischemic stroke. At rs3842788, AA genotype may increase the susceptibility of ischemic stroke. At rs689466, AA genotype may increase the susceptibility of large-artery atherosclerosis (LAA). COX - 1(rs1330344, rs3842788) and COX-2 rs689466 interacted in small vessel occlusion (SVO), but had no additive effect with ischemic stroke and other subtypes.


Assuntos
Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Predisposição Genética para Doença/genética , Acidente Vascular Cerebral/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/enzimologia , Aterosclerose/genética , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/enzimologia
5.
J Biomed Sci ; 26(1): 56, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31387590

RESUMO

BACKGROUND: Endothelial cell (EC) dysfunctions, including turnover enrichment, gap junction disruption, inflammation, and oxidation, play vital roles in the initiation of vascular disorders and atherosclerosis. Hemodynamic forces, i.e., atherprotective pulsatile (PS) and pro-atherogenic oscillatory shear stress (OS), can activate mechanotransduction to modulate EC function and dysfunction. This review summarizes current studies aiming to elucidate the roles of epigenetic factors, i.e., histone deacetylases (HDACs), non-coding RNAs, and DNA methyltransferases (DNMTs), in mechanotransduction to modulate hemodynamics-regulated EC function and dysfunction. OS enhances the expression and nuclear accumulation of class I and class II HDACs to induce EC dysfunction, i.e., proliferation, oxidation, and inflammation, whereas PS induces phosphorylation-dependent nuclear export of class II HDACs to inhibit EC dysfunction. PS induces overexpression of the class III HDAC Sirt1 to enhance nitric oxide (NO) production and prevent EC dysfunction. In addition, hemodynamic forces modulate the expression and acetylation of transcription factors, i.e., retinoic acid receptor α and krüppel-like factor-2, to transcriptionally regulate the expression of microRNAs (miRs). OS-modulated miRs, which stimulate proliferative, pro-inflammatory, and oxidative signaling, promote EC dysfunction, whereas PS-regulated miRs, which induce anti-proliferative, anti-inflammatory, and anti-oxidative signaling, inhibit EC dysfunction. PS also modulates the expression of long non-coding RNAs to influence EC function. i.e., turnover, aligmant, and migration. On the other hand, OS enhances the expression of DNMT-1 and -3a to induce EC dysfunction, i.e., proliferation, inflammation, and NO repression. CONCLUSION: Overall, epigenetic factors play vital roles in modulating hemodynamic-directed EC dysfunction and vascular disorders, i.e., atherosclerosis. Understanding the detailed mechanisms through which epigenetic factors regulate hemodynamics-directed EC dysfunction and vascular disorders can help us to elucidate the pathogenic mechanisms of atherosclerosis and develop potential therapeutic strategies for atherosclerosis treatment.


Assuntos
Aterosclerose/fisiopatologia , Células Endoteliais/fisiologia , Epigênese Genética , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Metilação de DNA/genética , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Hemodinâmica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Mecanotransdução Celular/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
6.
Int J Mol Sci ; 20(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277498

RESUMO

The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention.


Assuntos
Aterosclerose/enzimologia , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Inflamação/enzimologia , Lipoproteínas LDL/metabolismo , Óxido Nítrico Sintase/metabolismo , Animais , Humanos , Inflamação/patologia , Óxido Nítrico/metabolismo
7.
Life Sci ; 232: 116646, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302193

RESUMO

BACKGROUND: Some previous studies already explored associations between paraoxonase 1 (PON1) polymorphisms and atherosclerotic cardiovascular diseases (ASCVD), with conflicting findings. Here, we aimed to better analyze the relationship between PON1 polymorphisms and ASCVD in a larger combined population by performing a meta-analysis. METHODS: We searched Pubmed, Embase and Web of Science for related articles. We calculated odds ratio (OR) and 95% confidence interval (CI) to estimate whether there are genetic associations between PON1 polymorphisms and ASCVD. RESULTS: One hundred and nine studies were included for this meta-analysis. The PON1 rs854560 (17,220 cases and 18,570 controls, recessive comparison: OR = 0.83, 95%CI 0.72-0.96) and rs662 (30,717 cases and 54,894 controls, dominant comparison: OR = 0.82, 95% CI 0.77-0.89; recessive comparison: OR = 1.17, 95% CI 1.07-1.28; allele comparison: OR = 0.85, 95% CI 0.81-0.90) polymorphisms were both found to be significantly associated with susceptibility to ASCVD in general population. Subgroup analyses by ethnicity revealed similar significant findings for rs854560 polymorphism only in East Asians, while similar positive findings for rs662 polymorphism were observed in Caucasians, East Asians and South Asians. Subgroup analyses by type of disease indicated that the significant findings for rs854560 polymorphism were mainly driven by the ischemic stroke (IS) subgroup, whereas the positive results for rs662 polymorphism were mainly driven by the coronary artery disease (CAD) subgroup. CONCLUSIONS: In summary, this meta-analysis proved that PON1 rs854560 polymorphism could be used to identify individual with elevated susceptibility to IS, whereas rs662 polymorphism could be used to identify individual with elevated susceptibility to CAD.


Assuntos
Arildialquilfosfatase/genética , Aterosclerose/enzimologia , Aterosclerose/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Humanos
8.
Biomed Res Int ; 2019: 5747436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214617

RESUMO

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Inibidores Enzimáticos , Microssomos/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Obesidade Abdominal/tratamento farmacológico , Obesidade Abdominal/enzimologia
9.
High Blood Press Cardiovasc Prev ; 26(3): 199-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236902

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-related discoveries of the turn of the century have translated into substantial novelty in dyslipidemia treatment in the last 5 years. With chronic preventable atherosclerotic cardiovascular diseases (ASCVD) representing an epidemic of morbidity and mortality worldwide, low-density lipoprotein cholesterol (LDL-c) reduction represents a public health priority. By overcoming two major statin-related issues, namely intolerance and ineffectiveness, PCSK9 inhibitors have offered a safe and effective option in selected clinical settings where LDL-c reduction is required. Herein, we recapitulate recent findings, clinical applications, and ASCVD prevention potential of PCSK9 inhibition, with focus on anti-PCSK9 monoclonal antibodies, evolocumab and alirocumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/epidemiologia , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
10.
Biochimie ; 166: 77-83, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31181234

RESUMO

The cysteine protease legumain (asparaginyl endopeptidase, AEP) plays important roles in normal physiology but is also associated with several disorders, such as atherosclerosis, osteoporosis, cancer and neurodegenerative diseases. The functional roles of legumain have mainly been associated with the presence in lysosomes where legumain is active and mediates processing of multiple proteins, such as the conversion of single to double chain forms of cysteine cathepsins. However, in recent years, a number of studies point to extracellular roles of legumain in addition to the pivotal roles in the lysosomes. In this review, recent knowledge on novel extracellular functions of this protease will be addressed and new discoveries in relation to the diseases mentioned above will be presented.


Assuntos
Aterosclerose/enzimologia , Cisteína Endopeptidases/metabolismo , Lisossomos/enzimologia , Neoplasias/enzimologia , Doenças Neurodegenerativas/enzimologia , Osteoporose/enzimologia , Animais , Biomarcadores/metabolismo , Catepsinas/metabolismo , Humanos , Camundongos
11.
PLoS One ; 14(3): e0214150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889221

RESUMO

Myeloperoxidase (MPO) is a highly abundant protein within the neutrophil that is associated with lipoprotein oxidation, and increased plasma MPO levels are correlated with poor prognosis after myocardial infarct. Thus, MPO inhibitors have been developed for the treatment of heart failure and acute coronary syndrome in humans. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide PF-06282999 is a recently described selective small molecule mechanism-based inactivator of MPO. Here, utilizing PF-06282999, we investigated the role of MPO to regulate atherosclerotic lesion formation and composition in the Ldlr-/- mouse model of atherosclerosis. Though MPO inhibition did not affect lesion area in Ldlr-/- mice fed a Western diet, reduced necrotic core area was observed in aortic root sections after MPO inhibitor treatment. MPO inhibition did not alter macrophage content in and leukocyte homing to atherosclerotic plaques. To assess non-invasive monitoring of plaque inflammation, [18F]-Fluoro-deoxy-glucose (FDG) was administered to Ldlr-/- mice with established atherosclerosis that had been treated with clinically relevant doses of PF-06282999, and reduced FDG signal was observed in animals treated with a dose of PF-06282999 that corresponded with reduced necrotic core area. These data suggest that MPO inhibition does not alter atherosclerotic plaque area or leukocyte homing, but rather alters the inflammatory tone of atherosclerotic lesions; thus, MPO inhibition could have utility to promote atherosclerotic lesion stabilization and prevent atherosclerotic plaque rupture.


Assuntos
Acetamidas/farmacologia , Aterosclerose/tratamento farmacológico , Macrófagos/enzimologia , Peroxidase/antagonistas & inibidores , Placa Aterosclerótica/tratamento farmacológico , Pirimidinonas/farmacologia , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Peroxidase/genética , Peroxidase/metabolismo , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Receptores de LDL/deficiência , Receptores de LDL/metabolismo
12.
Biol Chem ; 400(6): 711-732, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-30864421

RESUMO

Atherosclerosis is a cardiovascular disease (CVD) known widely world wide. Several hypothesizes are suggested to be involved in the narrowing of arteries during process of atherogenesis. The oxidative modification hypothesis is related to oxidative and anti-oxidative imbalance and is the most investigated. The aim of this study was to review the role of oxidative stress in atherosclerosis. Furthermore, it describes the roles of oxidative/anti-oxidative enzymes and compounds in the macromolecular and lipoprotein modifications and in triggering inflammatory events. The reactive oxygen (ROS) and reactive nitrogen species (RNS) are the most important endogenous sources produced by non-enzymatic and enzymatic [myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADH) oxidase and lipoxygenase (LO)] reactions that may be balanced with anti-oxidative compounds [glutathione (GSH), polyphenols and vitamins] and enzymes [glutathione peroxidase (Gpx), peroxiredoxins (Prdx), superoxide dismutase (SOD) and paraoxonase (PON)]. However, the oxidative and anti-oxidative imbalance causes the involvement of cellular proliferation and migration signaling pathways and macrophage polarization leads to the formation of atherogenic plaques. On the other hand, the immune occurrences and the changes in extra cellular matrix remodeling can develop atherosclerosis process.


Assuntos
Aterosclerose/metabolismo , Estresse Oxidativo , Aterosclerose/enzimologia , Aterosclerose/patologia , Humanos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
13.
J Stroke Cerebrovasc Dis ; 28(6): 1732-1743, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878369

RESUMO

AIMS: The objective of this study was to perform a meta-analysis to evaluate the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and susceptibility to atherosclerosis (AS). METHODS: MEDLINE, EMBASE, and the ISI Web of Science were searched for all eligible published studies concerning the relationship of ACE gene polymorphism with AS without language restrictions. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate this relationship under different genetic models using meta-analytic methods. RESULTS: A total of 15 articles (16 studies) were involved in this meta-analysis. The D allele of the ACE gene had a nonsignificant increase in the risk of AS (D versus I: OR = 1.23, 95% CI, .98-1.53, P = .07; I2 = 87.2%, Pheterogeneity < .01). Compared with the II genotype, the DI (relative risk [RR]: 1.35, 95% CI: 1.09, 1.67, P < .01; I2 = 47.8%, Pheterogeneity = .017) and (DD + DI) (RR = 1.38, 95% CI: 1.04, 1.82, P = .02; I2 = 73.3%, Pheterogeneity < .01) genotype of ACE was associated with higher risk of AS, respectively. Subjects with the DD genotype showed a statistically nonsignificant trend toward greater risk of AS (RR = 1.53, 95% CI: .97, 2.43, P = .07; I2 = 88.6%, Pheterogeneity < .01). Further subgroup analyses showed that significant relationships were only found in Europeans under different gene polymorphism or different genotype models rather than Asians. CONCLUSIONS: The present meta-analysis indicated that the D allele in the ACE gene was associated with the risk of AS, especially in Europeans. Furthermore, increased copy number of D allele was significantly associated with increased AS risk in a dose-dependent manner.


Assuntos
Aterosclerose/genética , Mutação INDEL , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Idoso , Aterosclerose/diagnóstico , Aterosclerose/enzimologia , Aterosclerose/etnologia , Variações do Número de Cópias de DNA , Feminino , Dosagem de Genes , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Medição de Risco , Fatores de Risco
14.
Biochem Biophys Res Commun ; 512(2): 319-325, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30885430

RESUMO

Moderate alcohol consumption has been shown to reduce atherosclerosis-associated diseases. As shown in our earlier works, ethanol has a dose-dependent protective effects against endothelial cellular senescence by activating aldehyde dehydrogenase 2 (ALDH2) in vitro. However, whether ethanol administration possesses anti-atherosclerosis properties and whether ALDH2 is involved in the underlying mechanisms are unknown. In the present study, we revealed that the appropriate dose of ethanol reduced atherosclerotic plaque formation, and upregulated ALDH2 expression and activity in ApoE-/- mice. ALDH2 deficiency blocked the protection of ethanol against atherosclerotic plaque formation by inhibiting endothelium senescence. In contrast, Alda-1, which is a specific enzymatic agonist of ALDH2, enhanced the anti-senescence and anti-atherosclerosis effects of the appropriate dose of ethanol. Furthermore, following ALDH2 knockdown, resveratrol (an anti-aging compound) recovered the beneficial effects of ethanol against endothelial senescence in vitro. Thus, these results suggest that the appropriate dose of ethanol has protective effects against endothelial senescence and atherosclerosis by activating ALDH2.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Aterosclerose/prevenção & controle , Cardiotônicos/administração & dosagem , Etanol/administração & dosagem , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Aterosclerose/enzimologia , Aterosclerose/patologia , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Ativação Enzimática/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout para ApoE , Interferência de RNA
15.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1402-1409, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776415

RESUMO

The nuclear receptor liver X receptor (LXR) impacts on cholesterol metabolism as well as hepatic lipogenesis via transcriptional regulation. It is proposed that inhibition of the protein arginine methyltransferase 3 (PRMT3) uncouples these two transcriptional pathways in vivo by acting as a specific lipogenic coactivator of LXR. Here we validated the hypothesis that treatment with the allosteric PRMT3 inhibitor SGC707 will diminish the hepatic steatosis extent, while leaving global cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. For this purpose, 12-week old hyperlipidemic apolipoprotein E knockout mice were fed a Western-type diet for six weeks to induce both hepatic steatosis and atherosclerosis. The mice received 3 intraperitoneal injections with SGC707 or solvent control per week. Mice chronically treated with SGC707 developed less severe hepatic steatosis as exemplified by the 51% reduced (P < 0.05) liver triglyceride levels. In contrast, the extent of in vivo macrophage foam cell formation and aortic root atherosclerosis was not affected by SGC707 treatment. Interestingly, SGC707-treated mice gained 94% less body weight (P < 0.05), which was paralleled by changes in white adipose tissue morphology, i.e. reduction in adipocyte size and browning. In conclusion, we have shown that through PRMT3 inhibitor treatment specific functions of LXR involved in respectively the development of fatty liver disease and atherosclerosis can be uncoupled, resulting in an overall diminished hepatic steatosis extent without a negative impact on atherosclerosis susceptibility. As such, our studies highlight that PRMT3 inhibition may constitute a novel therapeutic approach to limit the development of fatty liver disease in humans.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Inibidores Enzimáticos/farmacologia , Fígado Gorduroso/prevenção & controle , Isoquinolinas/farmacologia , Proteína-Arginina N-Metiltransferases/genética , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/patologia , Regulação Alostérica/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Aterosclerose/enzimologia , Aterosclerose/etiologia , Aterosclerose/patologia , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Regulação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais , Triglicerídeos/metabolismo
16.
Clin Chim Acta ; 491: 24-29, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30639239

RESUMO

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a scavenger receptor of oxidized low-density lipoprotein (ox-LDL) found in various cells, plays a crucial role in the formation and progression of atherosclerotic plaques. Animal studies have suggested that LOX-1 mediates the balance between internalization and degeneration of endothelial cells, thereby contributing to various steps in the atherosclerotic process, from initiation to plaque rupture. Under pathological conditions, the extracellular domain of membrane bound LOX-1 can be largely proteolytically cleaved into a soluble form (sLOX-1), which is proportional and linked to the LOX-1 expression level. Circulating levels of sLOX-1 are regarded as a risk biomarker for plaque rupture and acute coronary syndrome (ACS). Recently, studies have shown that sLOX-1 is also elevated in patients with acute stroke and can be a predictive biomarker for acute stroke. With the discovery of the vital role of LOX-1 in atherosclerosis, there is growing focus on the influence of LOX-1 in atherosclerotic-related diseases, including coronary arterial disease(CAD), stroke, and other cardiovascular events. Genetic polymorphisms of LOX-1 have been investigated and have been found to modulate the risk of these diseases. Most polymorphisms have been found to be risk factors, except for the splicing isoform LOXIN. This review concludes with a discussion of the potential future applications of LOX-1 for atherosclerotic-related diseases.


Assuntos
Aterosclerose/enzimologia , Receptores Depuradores Classe E/metabolismo , Aterosclerose/genética , Humanos , Polimorfismo Genético , Receptores Depuradores Classe E/genética , Acidente Vascular Cerebral/enzimologia
17.
J Mol Cell Cardiol ; 126: 50-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448480

RESUMO

Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor.


Assuntos
Aterosclerose/enzimologia , Inflamação/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas F-Box/genética , Feminino , Variação Genética , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Bibliotecas de Moléculas Pequenas/farmacologia , Células THP-1
18.
Methods Mol Biol ; 1896: 31-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30474837

RESUMO

Senescence-associated ß-galactosidase (hereafter SA-ß-gal) staining has now been employed for more than 20 years to identify the presence of senescent cells (Dimri et al., Proc Natl Acad Sci U S A 92:9363-9367, 1995). These cells, characterized by a permanent cell-cycle arrest (Hayflick and Moorhead, Exp Cell Res 25:585-621, 1961) and the production of a distinct secretory phenotype of cytokines, chemokines, and proteases (Coppe et al., PLoS Biol 6:2853-2868, 2008), have received much attention in recent years for their impacts on diverse biological processes. Here we describe a method to identify and quantify the specific cells that become senescent in vivo using transmission electron microscopy after SA-ß-gal staining that can be used in countless scenarios.


Assuntos
Tecido Adiposo Branco/enzimologia , Aterosclerose/enzimologia , Senescência Celular , Túbulos Renais/enzimologia , Pericárdio/enzimologia , beta-Galactosidase/metabolismo , Tecido Adiposo Branco/citologia , Animais , Aterosclerose/patologia , Células Cultivadas , Túbulos Renais/citologia , Camundongos , Pericárdio/citologia
19.
Toxicol Appl Pharmacol ; 364: 45-54, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529164

RESUMO

Defective autophagy in vascular smooth muscle cells (VSMCs) is the principal cause of atherosclerosis. This study aimed to investigate the effect of astragaloside IV (AS-IV) on VSMCs autophagy. In vivo, ApoE-/- mice were fed with high-fat diet ad libitum for eight weeks, with or without AS-IV (25 mg/kg, daily). In vitro, human VSMCs were cultured and treated with ß-Glycerophosphate (10 mmol/L) and AS-IV (50 µg/ml). VSMCs autophagy, mineralization, expression of p-ERK1/2, p-mTOR, and autophagy-related proteins (LC3 II/I, p62, and Beclin 1) were detected. Increased autophagy and mineralization was observed in VSMCs in thoracic aorta of mice and in in vitro VSMCs model of atherosclerosis. AS-IV administration attenuated the autophagy and mineralization in VSMCs. Reverse expression profiles of H19 and DUSP5 were observed. AS-IV inhibited DUSP5 and autophagy-related proteins and increased expression of H19, level of p-ERK1/2 and p-mTOR. Further, autophagy and mineralization level in VSMCs were in line with DUSP5 expression level, but in contrast to H19, p-ERK1/2, and p-mTOR profiles. We demonstrated that AS-IV could attenuate autophagy and mineralization of VSMCs in atherosclerosis, which may be associated with H19 overexpression and DUSP5 inhibition.


Assuntos
Aterosclerose/prevenção & controle , Autofagia/efeitos dos fármacos , Fosfatases de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Calcificação Vascular/prevenção & controle , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fosforilação , Placa Aterosclerótica , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Calcificação Vascular/enzimologia , Calcificação Vascular/genética , Calcificação Vascular/patologia
20.
Circulation ; 139(1): 101-114, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29970364

RESUMO

BACKGROUND: Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions. METHODS: Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability, and amino acid profiling were also performed with human material. RESULTS: The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1ß. Consistent with the loss of H2S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and H2S levels, indicating its potential use as a biomarker for vascular disease. CONCLUSIONS: The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H2S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H2S are lost owing to the phosphorylation and inhibition of the enzyme.


Assuntos
Aterosclerose/enzimologia , Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/enzimologia , Cistationina gama-Liase/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Células Endoteliais/enzimologia , Sulfeto de Hidrogênio/metabolismo , Placa Aterosclerótica , Idoso , Idoso de 80 Anos ou mais , Animais , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/prevenção & controle , Catepsinas/metabolismo , Adesão Celular , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Cistationina gama-Liase/deficiência , Cistationina gama-Liase/genética , Modelos Animais de Doenças , Progressão da Doença , Proteína Semelhante a ELAV 1/genética , Células Endoteliais/patologia , Feminino , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Fosforilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais
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