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1.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073212

RESUMO

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as "wall shear stress (WSS)", and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.


Assuntos
Doença da Artéria Coronariana , Circulação Coronária , Células Endoteliais , Placa Aterosclerótica , Resistência ao Cisalhamento , Estresse Mecânico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Placa Aterosclerótica/terapia
2.
FASEB J ; 35(5): e21609, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33908659

RESUMO

Our purpose was to study the effect of hyperglycemia on macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling and its correlation with coronary atherosclerosis. A total of 135 patients with coronary heart disease (CHD) were divided into a stable CHD (SCHD) group (n = 30) and an acute myocardial infarction (AMI) group (n = 105) [nondiabetes mellitus (non-DM)-AMI, n = 60; DM-AMI, n = 45] from January to September 2020. The SYNTAX score and metabolic and inflammatory markers were quantified and compared. THP-1 cell studies and an animal study of coronary intimal hyperplasia were also carried out. We found that the DM-AMI group showed a higher SYNTAX score than the non-DM-AMI group (P < .05). The DM-AMI group showed the highest expression levels of TANK-binding kinase 1 (TBK1), hypoxia-inducible factor 1α (HIF-1α), and interleukin (IL)-17 and the lowest expression level of IL-10, followed by the non-DM-AMI group and the SCHD group (P < .05). THP-1 cell studies showed that BAY87-2243 (a HIF-1α inhibitor) reversed the increase in IL-17 and decrease in IL-10 expression induced by hyperglycemia. Amlexanox (a TBK1 inhibitor) reversed the increase in HIF-1α expression induced by hyperglycemia. Amlexanox treatment resulted in lower coronary artery intimal hyperplasia and a larger lumen area in a diabetic swine model. We conclude that hyperglycemia might aggravate the complexity of coronary atherosclerosis through activation of TBK1-HIF-1α-mediated IL-17/IL-10 signaling. Thus, TBK1 may be a novel drug therapy target for CHD complicated with DM.


Assuntos
Doença da Artéria Coronariana/patologia , Hiperglicemia/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Macrófagos/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Idoso , Animais , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Feminino , Humanos , Técnicas In Vitro , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Suínos
3.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923232

RESUMO

The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.


Assuntos
Coagulação Sanguínea , Doença da Artéria Coronariana/patologia , Proteínas de Membrana/metabolismo , Infarto do Miocárdio/patologia , Trombose/patologia , Doença da Artéria Coronariana/metabolismo , Humanos , Infarto do Miocárdio/metabolismo , Trombose/metabolismo
4.
Arterioscler Thromb Vasc Biol ; 41(5): e265-e279, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33761760
6.
Mayo Clin Proc ; 96(6): 1609-1621, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33775421

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and coronary atherosclerosis is the leading cause of death in the United States and worldwide. Endothelial dysfunction is the earliest clinically detectable form of atherosclerosis. Control of shared AF and coronary atherosclerosis risk factors improves both AF-free survival and vascular endothelial function. Decades of AF research have yielded fundamental insight into AF pathophysiology, but current pharmacological and catheter-based invasive AF therapies have limited long-term efficacy and substantial side effects, possibly because of incomplete understanding of underlying complex AF pathophysiology. We hereby discuss potential mechanistic links between endothelial dysfunction and AF (risk-factor-associated systemic inflammation and oxidative stress, myocardial ischemia, common gene variants, vascular shear stress, and fibroblast growth factor-23), explore a potential new vascular dimension to AF pathophysiology, highlight a growing body of evidence supporting an association between systemic vascular endothelial dysfunction, AF, and stroke, and discuss potential common effective therapies.


Assuntos
Fibrilação Atrial/etiologia , Endotélio Vascular/fisiopatologia , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Endotélio Vascular/patologia , Humanos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
7.
J Forensic Leg Med ; 79: 102148, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33706128

RESUMO

A complete case example of a fatal 2,4-dinitrophenol (DNP) overdose involving a 23-year-old male is described. Included are details of not only the patient's presentation symptoms and treatment, but also the subsequent findings of the coronial investigation process including the autopsy, post-mortem computed tomography (PMCT) scanning and toxicological analysis and results. The patient presented with elevated temperature, heart rate and blood pressure. Multiple treatments were conducted to counteract these symptoms, however the patient died approximately 1.5 hours after hospital admission and some 4.5 hours after the DNP was initially consumed. Autopsy revealed the presence of cardiovascular disease that was contributory to death and post-mortem computed tomography showed evidence of decompositional intravascular gas in the neck, head, face, lower abdomen, heart and hepatic systems. Toxicological analysis was completed by protein precipitation with methanol and subsequent instrumental analysis by LC/MS/MS in negative ion mode. The antemortem blood specimen showed the presence of tadalafil, two anabolic steroids and a DNP concentration of 110 mg/kg which is consistent with other reported DNP fatalities. Despite the small amount of time between the antemortem specimen collection and death, the DNP concentration identified in the femoral blood post-mortem specimen was comparably low (5.5 mg/kg). DNP concentrations also reduced during an extended period of specimen storage prior to analysis indicating some instability in biological specimens even when refrigerated or frozen. DNP was found to be distributed primarily in the aqueous tissues (blood, vitreous, bile) rather than solid matrices (liver, kidney, muscle).


Assuntos
2,4-Dinitrofenol/envenenamento , Fármacos Antiobesidade/envenenamento , Overdose de Drogas , Suicídio Consumado , 2,4-Dinitrofenol/análise , Fármacos Antiobesidade/análise , Bile/química , Doença da Artéria Coronariana/patologia , Gases , Humanos , Masculino , Músculo Esquelético/química , Mudanças Depois da Morte , Tomografia Computadorizada por Raios X , Corpo Vítreo/química , Adulto Jovem
8.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760184

RESUMO

It has previously been shown that the number of endothelial progenitor cells (EPCs) is negatively correlated with Syntax score in patients with coronary artery disease (CAD). However, the association between alterations in EPC function and Syntax score is still unknown. The present study evaluated the association between the activity of EPCs as well as endothelial function and Syntax score in patients with CAD and investigated the underlying mechanisms. A total of 60 patients with CAD were enrolled in 3 groups according to Syntax score, and 20 healthy subjects were recruited as the control group. The number and migratory, proliferative and adhesive activities of circulating EPCs were studied. The endothelial function was measured by flow­mediated dilatation (FMD) and the levels of nitric oxide (NO) in plasma or secreted by EPCs were detected. The number and activity of circulating EPCs were lower in patients with a high Syntax score, which was similar to the alteration in FMD. The level of NO in plasma or secreted by EPCs also decreased as Syntax score increased. There was a negative association between FMD or circulating EPCs and Syntax score. A similar association was observed between the levels of NO in plasma or secreted by EPCs and Syntax score. Patients with CAD who had a higher Syntax score exhibited lower EPC numbers or activity and weaker endothelial function, which may be associated with attenuated NO production. These findings provide novel surrogate parameters for evaluation of the severity and complexity of CAD.


Assuntos
Doença da Artéria Coronariana/sangue , Células Progenitoras Endoteliais/metabolismo , Óxido Nítrico/sangue , Idoso , Movimento Celular/genética , Proliferação de Células/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vasodilatação/genética
9.
Int Heart J ; 62(2): 371-380, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33731513

RESUMO

Coronary artery disease (CAD) is one of the heavy health burdens worldwide. Aberrant proliferation of vascular smooth muscle cells (VSMCs) contributes to the occurrence and development of CAD. This study aimed at exploring differentially expressed microRNAs (miRNAs) and their regulatory mechanisms in the development of CAD.The miRNA expression profile of GSE28858 was obtained from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEmiRNAs) between CAD and healthy control samples were analyzed using limma package in R. Target genes of DEmiRNAs were predicted, and a miRNA-target gene network was constructed. The relationship between miR-665 and transforming growth factor beta receptor 1 (TGFBR1) was selected for further analysis. The interaction between miR-665 and TGFBR1 was confirmed by dual luciferase reporter assay. Effects of miR-665 on cell viability and apoptosis of VSMCs were evaluated by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Besides, western blot assays for BCL2L11 and caspase 3 were also conducted.A total of 38 upregulated miRNAs and 28 downregulated miRNAs were identified. The expression level of miR-665 was significantly downregulated in patients with CAD. TGFBR1 was proved to be a target gene of miR-665. Besides, ectopic expression of miR-665 obviously inhibited VSMC growth and promoted VSMC apoptosis. TGFBR1 overexpression in VSMCs transfected with miR-665 mimic could restore the effect of miR-665 on the proliferation and apoptosis of VSMCs.MiR-665 might participate in the proliferation and apoptosis of VSMCs by targeting TGFBR1.


Assuntos
Doença da Artéria Coronariana/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Miócitos de Músculo Liso/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Regulação para Baixo , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , Miócitos de Músculo Liso/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/biossíntese , Regulação para Cima
10.
Int Heart J ; 62(2): 396-406, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33731537

RESUMO

Endothelial injury and inflammation have been found to be essential in the pathogenesis of coronary artery disease (CAD). Circulating exosomes are of great value as novel biomarkers for CAD. However, the role of circulating exosomes in the pathogenesis of CAD remains unclear. Thus, in this study, we aimed to examine whether circulating exosomes from CAD are involved in the endothelial injury and inflammation. The serum-derived exosomes were isolated from CAD and controls using an ExoQuick reagent, and these were then quantified by measuring the protein levels using BCA methods. The uptake of exosomes by human umbilical vein endothelial cells (HUVECs) was observed by laser scanning microscope and analyzed via flow cytometry. Then, HUVECs were treated with vehicle, exosomes from CAD (CAD-exo), and controls (ctrl-exo) in the absence and presence of vascular endothelial growth factor (VEGF). Cell viability, migration, and angiogenesis were evaluated using CCK-8 assay, scratch assay, and tube formation assay. Inflammatory factors including IL-1ß, IL-6, TNF-α, ICAM-1, and VCAM-1 levels were detected via qPCR. As per our findings, no significant differences were noted in uptake of ctrl-exo and CAD-exo by HUVECs. CAD-exo suppressed cell viability in a dose-dependent manner. Compared with ctrl-exo, CAD-exo-treated HUVECs significantly suppressed migration and angiogenesis. However, CAD-exo had a stronger inhibitory effect on VEGF-induced migration and angiogenesis compared with ctrl-exo. Moreover, IL-1ß, TNF-α, and ICAM-1 were determined to be significantly upregulated in HUVECs treated with CAD-exo, but IL-6 and VCAM-1 expressions were not affected. Overall, our results suggest that CAD-exo are involved in endothelial injury and inflammation, which may, in turn, cause endothelial dysfunction and potentially promote the development of CAD.


Assuntos
Doença da Artéria Coronariana/sangue , Exossomos/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Doença da Artéria Coronariana/patologia , Feminino , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade
11.
Mol Biol Rep ; 48(2): 1181-1191, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33566225

RESUMO

Atherosclerosis is the leading cause of death worldwide and has in part an inflammatory basis. Since epicardial adipose tissue (EAT) is in close contact with coronary arteries we hypothesized that an imbalance in thioredoxin-1 (TRX-1) and thioredoxin interacting protein (TXNIP) in EAT, activates NLRP3 inflammasome and promotes production of IL-1ß, leading to the development of atherosclerosis. Thirty-eight patients with coronary artery disease (CAD) and thirty patients with no clinical signs of atherosclerosis who underwent open-heart surgery for valve replacement were classified as CAD and control groups, respectively. Biopsy samples from EAT were collected and expression of TXNIP, TRX-1, NLRP3 and IL-1ß genes were assessed using qRT-PCR. Tissue protein levels of TXNIP and TRX-1 were determined by Western blotting while ELISA was applied to measure IL-1ß. Haematoxylin and eosin staining was used for histological examination. mRNA and protein levels of TXNIP in EAT were significantly higher in patients with CAD compared with control group, whereas CAD patients showed lower TRX-1 gene and protein expression. In addition, in CAD patients the NLRP3 gene expression was almost doubled and IL-1ß significantly increased at the both mRNA and protein levels. Enhancment in NLRP3 gene expression and TXNIP protein levels were accompanied with the increase in IL-1ß protein level whereas TRX-1 protein content showed a negative correlation with IL-1ß level. Concurrent increase in TXNIP, NLRP3, and IL-1ß suggests possible involvement of thioredoxin system in the activation of NLRP3 inflammasome, production of IL-1ß, and the presence of inflammation in CAD patients.


Assuntos
Aterosclerose/genética , Proteínas de Transporte/genética , Doença da Artéria Coronariana/genética , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Tiorredoxinas/genética , Tecido Adiposo , Idoso , Aterosclerose/patologia , Aterosclerose/cirurgia , Biópsia , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Inflamassomos/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Pericárdio/metabolismo , Pericárdio/patologia , Transdução de Sinais/genética , Cirurgia Torácica
12.
Arterioscler Thromb Vasc Biol ; 41(4): 1487-1503, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33567868
13.
Am J Hum Genet ; 108(3): 411-430, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33626337

RESUMO

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.


Assuntos
Doença da Artéria Coronariana/genética , Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença , Locos de Características Quantitativas/genética , Alelos , Cromatina/genética , Doença da Artéria Coronariana/patologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Genômica , Humanos , Fígado/metabolismo , Masculino , Anotação de Sequência Molecular , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Fatores de Risco
14.
Eur Rev Med Pharmacol Sci ; 25(1): 301-312, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33506919

RESUMO

OBJECTIVE: Coronary artery disease (CAD) is the main cause of mortality worldwide. How stable coronary artery disease (SCAD) progresses to acute myocardial infarction (AMI) is not known. This study was aimed to explore the differentially expressed genes (DEGs) and pathways involved in the progression of SCAD to AMI. MATERIALS AND METHODS: Publicly available gene-expression profiles (GSE71226, GSE97320, GSE66360) were downloaded from the Gene Expression Omnibus (GEO) database and integrated to identify DEGs. The GSE59867 dataset was further used to verify the result of screened DEGs. Functional-enrichment analyses, protein-protein interaction network, microRNA-transcription factor (TF)-mRNA regulatory network, and drug-gene network were visualized. RESULTS: Sixty common DEGs (CDEGs) were screened between the SCAD-Control group and AMI-Control group in the integrated dataset. Four upregulated DEGs were selected from GSE59867. Twenty hub genes were discovered, and three significant modules were constructed in the PPI network. The intersection of functional and pathway-enrichment analyses of 60 CDEGs and the module DEGs indicated that they were mainly involved in "inflammatory response", "immune response", and "cytokine-cytokine receptor interaction". A miRNA-TF-mRNA regulatory network comprised 87 miRNAs, 16 upregulated target DEGs and 7 TFs. CONCLUSIONS: We identified several important genes and miRNAs involved in the progression of SCAD to AMI: platelet activating factor receptor (PTAFR), aquaoporin-9 (AQP9), toll-like receptor-4 (TLR4), human constitutive androstane receptor-3 (HCAR3), leucine-rich-α2 glycoprotein-1 (LRG1), mothers Against Decapentaplegic Homolog 4 (SMAD4) and miRNA-149-5p, miRNA-6778-3p, and miRNA-520a-3p. Inflammation and the immune response had important roles in the progression from SCAD to AMI.


Assuntos
Biologia Computacional , Doença da Artéria Coronariana/metabolismo , Infarto do Miocárdio/metabolismo , Doença Aguda , Aquaporinas/genética , Aquaporinas/imunologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , MicroRNAs/genética , MicroRNAs/imunologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Mapas de Interação de Proteínas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/imunologia , Proteína Smad4/genética , Proteína Smad4/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia
15.
J Nutr Biochem ; 90: 108577, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388349

RESUMO

Diet quality and statin therapy are established modulators of coronary artery disease (CAD) progression, but their effect on the gastrointestinal tract and subsequent sequelae that could affect CAD progression are relatively unexplored. To address this gap, Ossabaw pigs (N = 32) were randomly assigned to receive isocaloric amounts of a Western-type diet (WD; high in saturated fat, refined carbohydrate, and cholesterol, and low in fiber) or a heart healthy-type diet (HHD; high in unsaturated fat, whole grains, fruits and vegetables, supplemented with fish oil, and low in cholesterol), with or without atorvastatin, for 6 months. At the end of the study, RNA sequencing with 100 base pair single end reads on NextSeq 500 platform was conducted in isolated pig jejunal mucosa. A two-factor edgeR analysis revealed that the dietary patterns resulted in three differentially expressed genes related to lipid metabolism (SCD, FADS1, and SQLE). The expression of these genes was associated with cardiometabolic risk factors and atherosclerotic lesion severity. Subsequent gene enrichment analysis indicated the WD, compared to the HHD, resulted in higher interferon signaling and inflammation, with some of these genes being significantly associated with serum TNF-α and/or hsCRP concentrations, but not atherosclerotic lesion severity. No significant effect of atorvastatin therapy on gene expression, nor its interaction with dietary patterns, was identified. In conclusion, Western and heart healthy-type dietary patterns differentially affect the expression of genes associated with lipid metabolism, interferon signaling, and inflammation in the jejunum of Ossabaw pigs.


Assuntos
Doença da Artéria Coronariana/terapia , Dieta Saudável/métodos , Dieta Ocidental , Inflamação/genética , Interferons/genética , Metabolismo dos Lipídeos/genética , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Atorvastatina/farmacologia , Fatores de Risco Cardiometabólico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Comportamento Alimentar , Feminino , Expressão Gênica , Coração , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/metabolismo , Interferons/metabolismo , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Masculino , Suínos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Metabolism ; 117: 154710, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33485865

RESUMO

OBJECTIVE: The current study was aimed to investigate the involvement of endoplasmic reticulum stress (ERS)-mediated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in advanced glycation end products (AGEs)-exacerbated coronary microvascular dysfunctions (CMD) in non-obstructive coronary artery disease (NoCAD). METHODS AND MATERIALS: ob/ob-/- mice were used as NoCAD animal model which were exposed to AGEs by intraperitoneal injections. Animal CMD was evaluated by coronary flow velocity reserve (CFVR). A viral vector carrying perk-siRNA was used to silence PERK in vivo and in vitro studies. Cell apoptosis was detected by TUNEL. Immunofluorescent staining was used to assess CD42c-positive cell number in cardiac sections and NFATc4 translocation in CMECs. Real-time PCR and Western blotting were used to evaluate the gene expression levels. Cytokine and AGEs concentrations were determined by ELISA. Enzymatic activity of CaN was measured by a colorimetric method. A registered cross sectional study consisted of 77 patients diagnosed as NoCAD was used to analyze the association between diabetes and CMD which was measured by index of microvascular resistance (IMR) with a pressure wire system. RESULTS: Significant CMD was found in NoCAD mice compared with healthy control. AGEs exposure exacerbated CMD in NoCAD animals which was improved by PERK silencing. Phosphorylation of PERK, nuclear translocation of nuclear factor of activated T-cells (NFAT)c4, enzymatic activity of calcineurin (CaN), expression levels of Fas/FasL, production of interleukin (IL)6, tumor necrosis factor (TNF)α, cyclooxygenase (COX)2, thromboxane B (TXB)2 as well as apoptosis were suppressed by PERK silencing in cardiac microcirculation endothelial cells (CMECs) isolated from AGEs-exposed NoCAD mice and AGEs-treated primary CMECs. PERK silencing also reduced CD42c-postive cells number in cardiac tissue from AGEs-exposed NoCAD mice. CONCLUSION: Diabetes was associated with CMD in NoCAD. AGEs fostered in diabetes exacerbated CMD by activating ERS-mediated PERK/CaN/NFATc4 signaling in CMECs. IMR values increased significantly in NoCAD patients complicated with diabetes, which were significantly and positively correlated with serum AGEs concentrations.


Assuntos
Doença da Artéria Coronariana/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Microcirculação/fisiologia , Transdução de Sinais/fisiologia , eIF-2 Quinase/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular , Doença da Artéria Coronariana/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Estudos Transversais , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retículo Endoplasmático/fisiologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/fisiologia
18.
J Clin Ultrasound ; 49(3): 218-226, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33051899

RESUMO

PURPOSE: To assess carotid intima-media thickness (IMT), carotid plaques, and cardiovascular risk factors in patients with suspected coronary artery disease (CHD) to determine their association and predictive value for CHD. METHODS: We performed duplex Doppler ultrasonography of the carotid arteries and coronary angiography or CT in 480 patients with suspected CHD, and investigated their personal and medical histories. Patients were then assigned to the CHD or the control group depending on the presence of coronary lesions. Ultrasonography was performed the morning after admission prior to any treatment, coronary angiography, or CT. RESULTS: Carotid plaques were mainly distributed in the common carotid artery bifurcation, with a significant difference between the CHD and control groups. Plaque incidence (80%) and IMT were significantly higher (P < .001 and P = .012, respectively) in the CHD (80% and 0.84 ± 0.21 mm) than in the control group (49% and 0.76 ± 0.18 mm). The factors significantly associated with CHD were introduced into a multivariate regression model. Male subject (OR = 1.569, 95%CI 1.004-2.453; P = .048) and plaque burden (OR = 0.457, 95%CI 0.210-0.993; P = .048) were significant predictors for CHD occurrence. The presence of carotid plaques performed significantly better than IMT and the Framingham risk score for predicting CHD lesions (P < .001 for both). CONCLUSIONS: CHD patients showed higher percentage of clinical (plaques) or subclinical (IMT) carotid artery wall change, and the presence of carotid plaques showed better predictive value than IMT and Framingham risk score for the presence of coronary artery lesions.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Ultrassonografia
19.
Hosp Pract (1995) ; 49(1): 12-21, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32859138

RESUMO

Myocardial infarction (MI) in the absence of obstructive coronary artery disease (MINOCA) is prevalent in around 5% of acute myocardial infarction (AMI) presentations. MINOCA is a heterogeneous entity with many different etiologies. It is important for health care providers to familiarize themselves with the disease process, presentation, and possible underlying causes in order to guide appropriate management strategies. In this article, the authors review the contemporary definition, etiologies and assessment, and management for AMI patients with MINOCA.


Assuntos
Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Aneurisma Dissecante/complicações , Cardiomiopatia Hipertrófica/complicações , Fármacos Cardiovasculares/uso terapêutico , Doença da Artéria Coronariana/patologia , Circulação Coronária/fisiologia , Vasoespasmo Coronário/complicações , Vasos Coronários/patologia , Humanos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/etiologia , Miocardite/complicações , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores de Risco , Índice de Gravidade de Doença , Cardiomiopatia de Takotsubo/complicações , Tromboembolia/complicações
20.
Arterioscler Thromb Vasc Biol ; 41(1): 446-457, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232201

RESUMO

OBJECTIVE: Coronary artery disease (CAD) is associated with a compensatory switch in mechanism of flow-mediated dilation (FMD) from nitric oxide (NO) to H2O2. The underlying mechanism responsible for the pathological shift is not well understood, and recent reports directly implicate telomerase and indirectly support a role for autophagy. We hypothesize that autophagy is critical for shear stress-induced release of NO and is a crucial component of for the pathway by which telomerase regulates FMD. Approach and Results: Human left ventricular, atrial, and adipose resistance arterioles were collected for videomicroscopy and immunoblotting. FMD and autophagic flux were measured in arterioles treated with autophagy modulators alone, and in tandem with telomerase-activity modulators. LC3B II/I was higher in left ventricular tissue from patients with CAD compared with non-CAD (2.8±0.2 versus 1.0±0.2-fold change; P<0.05), although p62 was similar between groups. Shear stress increased Lysotracker fluorescence in non-CAD arterioles, with no effect in CAD arterioles. Inhibition of autophagy in non-CAD arterioles induced a switch from NO to H2O2, while activation of autophagy restored NO-mediated vasodilation in CAD arterioles. In the presence of an autophagy activator, telomerase inhibitor prevented the expected switch (Control: 82±4%; NG-Nitro-l-arginine methyl ester: 36±5%; polyethylene glycol catalase: 80±3). Telomerase activation was unable to restore NO-mediated FMD in the presence of autophagy inhibition in CAD arterioles (control: 72±7%; NG-Nitro-l-arginine methyl ester: 79±7%; polyethylene glycol catalase: 38±9%). CONCLUSIONS: We provide novel evidence that autophagy is responsible for the pathological switch in dilator mechanism in CAD arterioles, demonstrating that autophagy acts downstream of telomerase as a common denominator in determining the mechanism of FMD.


Assuntos
Tecido Adiposo/irrigação sanguínea , Arteríolas/enzimologia , Autofagia , Doença da Artéria Coronariana/enzimologia , Vasos Coronários/enzimologia , Telomerase/metabolismo , Vasodilatação , Adulto , Idoso , Arteríolas/patologia , Arteríolas/fisiopatologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Lisossomos/enzimologia , Lisossomos/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Transdução de Sinais
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