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BACKGROUND AND AIM: Patients with cholelithiasis (CL) or cholecystectomy (CE) would have more chances of getting colorectal adenoma (CRA) or cancer (CRC). We aimed to figure out the effects of gut microbiota and bile acid on colorectal neoplasm in CL and CE patients. METHODS: This was a retrospective observational study that recruited 514 volunteers, including 199 people with normal gallbladders (normal), 152 CL, and 163 CE patients. Discovery cohort was established to explore the difference in gut microbiota through 16S rRNA and metagenomics sequencing. Validation cohort aimed to verify the results through quantitative polymerase chain reaction (qPCR). RESULTS: Significant enrichment of Escherichia coli was found in patients with cholelithiasis or cholecystectomy both in the discovery cohort (16S rRNA sequencing, PNormal-CL = 0.013, PNormal-CE = 0.042; metagenomics sequencing, PNormal-CE = 0.026) and validation cohort (PNormal-CL < 0.0001, PNormal-CE < 0.0001). Pks+ E. coli was found enriched in CL and CE patients through qPCR (in discovery cohort: PNormal-CE = 0.018; in validation cohort: PNormal-CL < 0.0001, PNormal-CE < 0.0001). The differences in bile acid metabolism were found both through Tax4Fun analysis of 16S rRNA sequencing (Ko00120, primary bile acid biosynthesis, PNormal-CE = 0.014; Ko00121, secondary bile acid biosynthesis, PNormal-CE = 0.010) and through metagenomics sequencing (map 00121, PNormal-CE = 0.026). The elevation of serum total bile acid of CE patients was also found in validation cohort (PNormal-CE < 0.0001). The level of serum total bile acid was associated with the relative abundance of pks+ E. coli (r = 0.1895, P = 0.0012). CONCLUSIONS: E. coli, especially pks+ species, was enriched in CL and CE patients. Pks+ E. coli and bile acid metabolism were found associated with CRA and CRC in people after cholecystectomy.
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Ácidos e Sais Biliares , Colecistectomia , Colelitíase , Neoplasias Colorretais , Escherichia coli , Humanos , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/sangue , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/etiologia , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Colelitíase/microbiologia , Colelitíase/etiologia , Colelitíase/cirurgia , Microbioma Gastrointestinal , Adulto , Carcinogênese , RNA Ribossômico 16S/genética , IdosoRESUMO
OBJECTIVE: In a previous study, we established diabetic and nondiabetic minipig models with coronary artery in-stent restenosis (ISR). Mass spectrometry showed that high-mobility group box (HMGB) 2 level was higher in ISR than in non-ISR tissue from diabetic minipigs. We here investigated whether serum HMGB2 levels were related to ISR in coronary artery disease patients. The effect of HMGB2 was evaluated in mice with femoral artery wire injury and in human aortic smooth muscle cells. APPROACH AND RESULTS: From 2513 patients undergoing coronary artery intervention and follow-up angiography at ≈1 year, 262 patients were diagnosed with ISR, and 298 patients with no ISR were randomly included as controls. Serum HMGB2 levels were significantly higher in patients with ISR than in those without ISR and were associated with ISR severity. Multivariable logistic regression analysis showed that HMGB2 level was independently associated with ISR. In experiments, HMGB2 expression was increased in vascular tissue after injury. Perivascular HMGB2 administration promoted injury-induced neointimal hyperplasia in C57Bl/6 mice compared with in the control, whereas such pathophysiological features were attenuated in Hmgb2-/- mice. Mechanistically, HMGB2 enhanced neointimal hyperplasia in mice and proliferation and migration in human aortic smooth muscle cells by inducing reactive oxygen species through increased p47phox phosphorylation. Knocking down p47phox, however, inhibited HMGB2-induced effects in human aortic smooth muscle cells. Finally, HMGB2-induced effects were significantly declined in receptor of advanced glycation end products knockdown or deficient cells, but not in Toll-like receptor 4 knockdown or deficient cells. CONCLUSIONS: Serum HMGB2 levels were associated with ISR in patients. HMGB2 promoted neointimal hyperplasia in mice with arterial wire injury through reactive oxygen species activation.
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Movimento Celular , Proliferação de Células , Doença da Artéria Coronariana/terapia , Reestenose Coronária/etiologia , Proteína HMGB2/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima , Intervenção Coronária Percutânea/efeitos adversos , Lesões do Sistema Vascular/sangue , Idoso , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Reestenose Coronária/sangue , Reestenose Coronária/diagnóstico por imagem , Modelos Animais de Doenças , Feminino , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Predisposição Genética para Doença , Proteína HMGB2/deficiência , Proteína HMGB2/genética , Humanos , Hiperplasia , Modelos Logísticos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Análise Multivariada , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NADPH Oxidases/metabolismo , Intervenção Coronária Percutânea/instrumentação , Fenótipo , Fosforilação , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fatores de Risco , Transdução de Sinais , Stents , Suínos , Porco Miniatura , Transfecção , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologiaRESUMO
High-mobility group box (HMGB) family is related to inflammatory diseases. We investigated whether serum HMGB2 levels are related to myocardial infarction (MI) severity and major adverse cardiac events (MACE) during MI. We included 432 consecutive patients with ST-segment elevation myocardial infarction and 312 controls. Serum HMGB2 levels were significantly higher in MI patients than in controls. Increased HMGB2 levels were associated with MACE and negatively with ejection fraction in MI patients. HMGB2 was an independent determinant of MACE in logistic regression analysis. HMGB2 protein (10 µg) or saline was injected intramyocardially in MI rats, with or without coadministration of the NADPH oxidase inhibitor apocynin. After 72 h, pathological, echocardiographic, and hemodynamic examinations showed that HMGB2 increased infarct size and worsened cardiac function in MI rats. Moreover, HMGB2 administration enhanced reactive oxygen species (ROS) production, cell apoptosis, inflammation, and autophagosome clearance impairment, which were attenuated by coadministration of apocynin or knock down of receptor for advanced glycation end products (RAGE). In conclusion, increased serum HMGB2 levels are associated with MI severity and MACE at 1 mo. HMGB2 promotes myocardial ischemic injury in rats and hypoxic H9C2 cell damage via ROS provoked by RAGE.NEW & NOTEWORTHY We demonstrate that serum high-mobility group box 2 is associated with major adverse cardiac events at 1 mo in myocardial infarction patients. Mechanistically, high-mobility group box 2 promotes reactive oxygen species production via receptor for advanced glycation end products signaling in ischemic myocardium, thereby aggravating cell apoptosis, inflammation, and autophagosome clearance impairment. This study reveals that high-mobility group box 2 is a novel factor enhancing ischemic injury in myocardial infarction.
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Proteína HMGB2/sangue , Proteína HMGB2/toxicidade , Isquemia Miocárdica/sangue , Espécies Reativas de Oxigênio/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Acetofenonas/farmacologia , Idoso , Animais , Apoptose , Linhagem Celular , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Proteína HMGB2/genética , Coração/fisiopatologia , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , NADPH Oxidases/antagonistas & inibidores , Fagossomos , Ratos , Ratos Sprague-Dawley , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Volume SistólicoRESUMO
Endothelial hyper-permeability is a major determinant factor that contributes to the accelerated development of atherosclerotic lesions at hemodynamically disturbed sites. Previously, we showed that C1q/TNF related protein (CTRP) 1 promotes endothelium-leukocyte interactions and inflammatory responses in vascular cells. Here, we sought to investigate the role of CTRP1 in modulation of endothelial permeability under disturbed flow condition. By using en face staining of mouse aorta, we found CTRP1 expression was significantly increased in vascular endothelial cells under disturbed flow as compared to steady laminar flow. Vascular permeability to Evans blue dye was notably enhanced in CTRP1 knockin mice as compared to wild type animals, whereas aortic hyper-permeability at disturbed sites was remarkably restored after deletion of CTRP1. In cultured endothelial cells, treatment of CTRP1 led to increased permeability to fluorescent-labelled dextran and apparent formation of paracellular holes as observed after disturbed flow exposure, which was evidently reduced in the presence of a CTRP1-specific neutralizing antibody. Mechanistically, we found activation of VEGFR2 by CTRP1 might be involved in vascular hyper-permeability under disturbed flow condition. Taken together, this study suggests that CTRP1 is a mechano-sensitive proinflammatory factor that mediates disturbed flow-induced vascular barrier dysfunction. Inhibition of CTRP1 may inhibit the pathogenesis of atherosclerosis at early stage.
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Adipocinas/metabolismo , Aorta/fisiologia , Permeabilidade Capilar , Endotélio Vascular/fisiologia , Proteínas/metabolismo , Adipocinas/análise , Adipocinas/genética , Animais , Velocidade do Fluxo Sanguíneo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Técnicas de Introdução de Genes , Células Endoteliais da Veia Umbilical Humana , Camundongos Knockout , Proteínas/análise , Proteínas/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
AIMS: We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS: We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 µg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION: C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice.
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Aterosclerose , Adipocinas , Animais , Antígenos CD , Apolipoproteínas E , Caderinas , Humanos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , ProteínasRESUMO
BACKGROUND: Our previous study suggested that heart-type fatty acid-binding protein (HFABP) levels were greatly elevated in the conditioned medium of explant culture of in-stent restenosis (ISR) tissue from diabetic minipigs compared with those of non-ISR tissue. We here verified this result in animal tissues and investigated the impact of HFABP overexpression in human aortic smooth muscle cells (hASMCs). METHODS AND RESULTS: In Western blot and real-time RT-PCR, HFABP protein and mRNA levels were significantly higher in ISR than in non-ISR tissues from minipigs, and higher in the ISR tissue from diabetic minipigs than that from nondiabetic minipigs. The mRNA microarray and cellular effects of hASMC retroviral overexpression of HFABP and vector was analyzed. Compared with vector, HFABP transduction activates multiple signaling pathways (e.g. adipokine, TGF-ß, Toll-like receptor, Wnt, Hedgehog, ErbB and Notch) and promotes inflammation, growth and migration in hASMCs whereas the knockdown of HFABP by small hairpin RNA attenuates these effects. CONCLUSION: HFABP expression is significantly higher in ISR tissue than in non-ISR tissue from diabetic and nondiabetic minipigs. Overexpression of HFABP induces multiple pathway-related promotion of inflammation, growth and migration in vascular SMCs, suggesting a potential role in coronary artery ISR.
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Movimento Celular , Proliferação de Células , Reestenose Coronária/metabolismo , Diabetes Mellitus Experimental/complicações , Proteínas de Ligação a Ácido Graxo/metabolismo , Inflamação/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Intervenção Coronária Percutânea/instrumentação , Stents , Animais , Células Cultivadas , Reestenose Coronária/etiologia , Reestenose Coronária/genética , Reestenose Coronária/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/genética , Redes Reguladoras de Genes , Humanos , Inflamação/etiologia , Inflamação/genética , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Intervenção Coronária Percutânea/efeitos adversos , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Suínos , Porco Miniatura , Fatores de Tempo , Técnicas de Cultura de Tecidos , Transfecção , Regulação para CimaRESUMO
OBJECTIVE: We aimed to uncover the protein changes of coronary artery in-stent restenosis (ISR) tissue in minipigs with and without streptozotocin-induced diabetes mellitus by quantitative 2-dimensional fluorescence in-gel electrophoresis (2D-DIGE), and to investigate the influences of crucial proteins identified, particularly adipocyte fatty acid binding protein (AFABP), in human arterial smooth muscle cells. METHODS AND RESULTS: Sirolimus-eluting stents were implanted in the coronary arteries of 15 diabetic and 26 nondiabetic minipigs, and angiography was repeated after 6 months. The intima tissue of significant ISR and non-ISR segments in both diabetic and nondiabetic minipigs was analyzed by 2D-DIGE and MALDI-TOF/TOF mass spectrometry. AFABP level was significantly increased in ISR tissue than in non-ISR tissue in both diabetic and nondiabetic minipigs, with level being higher in diabetic ISR than in nondiabetic ISR tissue. In human arterial smooth muscle cells, overexpression of AFABP significantly altered phenotype and promoted growth and migration, with effects more prominent in high-glucose than in low-glucose medium, whereas AFABP knockdown inhibited these effects. AFABP overexpression increased reactive oxygen species production by upregulating the expression of NADPH oxidase subunits Nox1, Nox4, and P22 through multiple pathways, with elevation of downstream gene cyclin D1, matrix metalloproteinase-2, and monocyte chemoattractant protein-1. However, AFABP-induced effects were inhibited by diphenyleneiodonium, pathway inhibitors, and small interfering RNA. In addition, the supernatant from AFABP-expressing human arterial smooth muscle cells and recombinant AFABP also promoted cellular growth and migration. CONCLUSIONS: This study has demonstrated that AFABP is significantly increased in coronary artery ISR segments of both diabetic and nondiabetic minipigs. Increased AFABP expression and secretory AFABP of human arterial smooth muscle cells promote growth and migration via reactive oxygen species-mediated activation.
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Movimento Celular , Proliferação de Células , Reestenose Coronária/metabolismo , Eletroforese em Gel Bidimensional , Proteínas de Ligação a Ácido Graxo/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Fármacos Cardiovasculares/administração & dosagem , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Reestenose Coronária/etiologia , Reestenose Coronária/genética , Reestenose Coronária/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Stents Farmacológicos , Inibidores Enzimáticos/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Fluorescência , Glucose/metabolismo , Humanos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Neointima , Estresse Oxidativo , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Fenótipo , Interferência de RNA , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Sirolimo/administração & dosagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Suínos , Porco Miniatura , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo , Transfecção , Regulação para CimaRESUMO
Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
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OBJECTIVE: To clarify the endoscopic, clinicopathological, and growth characteristics of minute gastric cancer (MGC) and to improve its detection rate. METHODS: Patients with early gastric cancer who underwent endoscopic submucosal dissection from July 2012 to September 2021 were retrospectively reviewed. MGC was defined as gastric cancer of 5 mm or less in size. Preoperative and postoperative endoscopic and pathological data were collected and analyzed. Follow-up information was collected until 9 April 2022. RESULTS: Eighty patients were enrolled, with 82 lesions observed under endoscopy and 87 diagnosed histopathologically. All patients received en bloc and curative resection. Compared with the time point when the last endoscopic examiniation prior to lesion deteciton was performed (t0), 64.29% of patients with MGC had disease progression at lesion detection (t1). However, 21.43% showed normal or only atrophic changes under white-light endoscopy, and their lesions were diagnosed accidentally by random biopsy. The majority of MGC lesions presented as type IIc and reddish, and 95.00% of cases had well-differentiated tubular adenocarcinoma. The mean growth rate of MGC was 0.0071 mm/day, and it took an average of 3.42 years to grow to 5 mm. There was no significant difference in the depth of invasion between the low cellular atypia group and the high cellular atypia group. CONCLUSIONS: Type IIc and reddish appearance are main endoscopic features of MGC. For cases with no obvious endoscopic changes, multipoint biopsy is helpful. MGC is mostly well differentiated and grows relatively slowly; therefore, MGC can still have a chance to be identified and resected curatively if it is missed diagnosed.
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Adenocarcinoma , Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Humanos , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Endoscopia Gastrointestinal , Adenocarcinoma/patologia , Mucosa Gástrica/patologiaRESUMO
Aberrant changes in endothelial phenotype and morphology are considered to be initial events in the pathogenesis of atherosclerosis. Direct observation of the intact endothelium will provide valuable information for understanding the cellular and molecular events in the dysfunctional endothelial cells. Here, we describe a modified en face immunofluorescence staining technique which enables scientists to obtain clear images of the intact endothelial surface and analyze the molecule expression patterns in situ. The method is simple and reliable for observing the entire endothelial monolayer at different sites of the aorta. This technique may be a promising tool for understanding the pathophysiology of atherosclerosis, especially at an early stage.
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Aorta/citologia , Endotélio Vascular/citologia , Imunofluorescência/métodos , Animais , Aorta/metabolismo , Aterosclerose/patologia , Células Cultivadas , Endotélio Vascular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
High-density lipoprotein (HDL) confers protection against cardiovascular disease partly attributable to its robust anti-oxidant activities, which is largely impaired in diabetic conditions. In this study, we analyzed the anti-oxidant activity of HDL, as represented by the arylesterase activity of paraoxonase 1 (PON1) in HDL particles, in 216 consecutive HF patients with (n = 79) or without (n = 137) type 2 diabetes, and age- and gender-matched 112 diabetic and 189 non-diabetic non-HF controls. We found arylesterase activity was significantly decreased in patients with than without HF, and was further decreased when comorbid with diabetes. After adjusting for conventional risk factors and apolipoprotein A-I levels, arylesterase activity remained correlated positively with left ventricular ejection fraction in diabetic (r = 0.325, P = 0.020) but not non-diabetic patients (r = 0.089, P = 0.415), and negatively with NT-proBNP and NYHA functional class in both subgroups. In regression analyses, a higher risk of HF was observed in diabetic than non-diabetic patients when having low arylesterase activities. In conclusion, our data demonstrate that impaired serum arylesterase activity in patients with HF is further reduced when comorbid with diabetes. The relationship of impaired arylesterase activity to HF is especially enhanced in diabetic patients.
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Arildialquilfosfatase/sangue , Hidrolases de Éster Carboxílico/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Insuficiência Cardíaca Sistólica/complicações , Insuficiência Cardíaca Sistólica/enzimologia , Lipoproteínas HDL/sangue , Comorbidade , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Insuficiência Cardíaca Sistólica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Função Ventricular EsquerdaRESUMO
Background: Chronic inflammatory disorders and dyslipidemia in type 2 diabetes mellitus (T2DM) are essential contributors to the development of atherosclerotic cardiovascular disease. Monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel and simple measure associated positively with the body inflammatory and oxidative stress status. However, little is known regarding the role of MHR in evaluating carotid intima-media thickness (CIMT), a surrogate predictor of subsequent vascular events, especially in diabetic patients. Methods: A total of 494 patients with T2DM and 1,848 non-diabetic subjects were consecutively enrolled in study 1. Correlation between MHR and CIMT was compared between diabetic and non-diabetic subjects. In study 2, a total of 110 T2DM patients from study 1 with normal basal CIMT and a follow-up ultrasonography at 12 months were enrolled. The predictive role of MHR on CIMT progression in diabetic patients was analyzed. Results: In study 1, MHR was higher in patients with T2DM than non-diabetic subjects (p < 0.001). After adjustment for confounding risk factors, MHR remained correlated significantly with CIMT in diabetic (r = 0.172, p = 0.001) but not non-diabetic (r = 0.006, p = 0.813) subjects. Logistic regression analyses demonstrated that MHR is superior to traditional lipid parameters in association with elevated CIMT in diabetic patients. In study 2, MHR at baseline was positively correlated with change in CIMT (r = 0.313, p = 0.001). Basal MHR was independently associated with change in CIMT [ß = 0.059, (95% CI: 0.012-0.105), p = 0.014] in multivariate linear regression analysis. Conclusions: Our study suggests that MHR is a convenient and effective measure in prediction of the presence and progression of subclinical carotid atherosclerosis in patients with T2DM.
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The data presented in this article are related to the research article entitled "Increased serum TREM-1 level is associated with in-stent restenosis, and activation of TREM-1 promotes inflammation, proliferation and migration in vascular smooth muscle cells" (Wang et al., 2017) [1], which demonstrated that TREM-1 is expressed on vascular smooth cells (VSMCs) and promotes inflammation, proliferation and migration in cultured VSMCs. In this dataset, the expression of TREM-1 in leukocytes and endothelial cells of carotid artery after ligation was evaluated. The effect of TREM-1 on stenosis was analyzed in cultured human saphenous veins (HSVs) that spontaneously undergo remodeling which involves VSMC proliferation and migration.
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BACKGROUND AND AIMS: Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined. METHODS: Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo. RESULTS: We found CTRP5 serum levels were higher in patients with than without CAD (247.26⯱â¯61.71 vs. 167.81⯱â¯68.08â¯ng/mL, pâ¯<â¯0.001), and were positively correlated with the number of diseased vessels (Spearman's râ¯=â¯0.611, pâ¯<â¯0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis. CONCLUSIONS: These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX.
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Araquidonato 12-Lipoxigenase/sangue , Araquidonato 15-Lipoxigenase/sangue , Aterosclerose/metabolismo , Colágeno/fisiologia , Lipoproteínas LDL/metabolismo , Oxigênio/metabolismo , Idoso , Angina Estável/sangue , Animais , Aorta/metabolismo , Colágeno/sangue , Doença da Artéria Coronariana/sangue , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Placa Aterosclerótica/sangue , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , TranscitoseRESUMO
BACKGROUND AND AIMS: In-stent restenosis (ISR) remains a major limitation of percutaneous coronary intervention despite improvements in stent design and pharmacological agents, whereas the mechanism of ISR has not been fully clarified. In the present study, we sought to investigate the potential association of serum soluble TREM-1 (sTREM-1) levels with the incidence of ISR. The role of TREM-1 was evaluated in cultured vascular smooth muscle cells (VSMCs). METHODS: Out of 1683 patients undergoing coronary intervention and follow-up coronary angiography after approximately one year, 130 patients were diagnosed with ISR, and 150 gender- and age-matched patients with no ISR were randomly included as controls. Levels of sTREM-1 were determined by ELISA. The role of TREM-1 signaling in the activation of VSMCs was tested. RESULTS: Serum sTREM-1 concentrations were significantly elevated in patients with than without ISR. Multivariable logistic regression analysis showed that sTREM-1, besides conventional factors, was independently associated with the incidence of ISR. Evident expression of TREM-1 in VSMCs was detected in the neointimal and medial layers of stenotic lesions of mouse carotid ligation models. In cultured VSMCs, expression of TREM-1 was significantly induced upon exposure to lipopolysaccharide. Blocking of TREM-1 with a synthetic inhibitory peptide LP17 dramatically inhibited, whereas TREM-1-activating antibody promoted cellular inflammation, proliferation and migration in VSMCs. CONCLUSIONS: These data suggest that TREM-1 is a predictive biomarker of ISR and an important mediator of cellular inflammation, migration, and proliferation in VSMCs. Pharmacological inhibition of TREM-1 may serve as a promising approach to attenuate the progression of ISR.
Assuntos
Reestenose Coronária/sangue , Miócitos de Músculo Liso/citologia , Stents/efeitos adversos , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Idoso , Animais , Aorta/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Quimiotaxia , Reestenose Coronária/metabolismo , Feminino , Humanos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Análise Multivariada , Músculo Liso Vascular/citologia , Razão de Chances , Intervenção Coronária Percutânea/efeitos adversos , Veia Safena/metabolismo , Transdução de Sinais , Túnica Íntima/metabolismo , Túnica Média/metabolismoRESUMO
BACKGROUND AND AIMS: Macrophage is a major contributor to the development of atherosclerosis by taking up deposited lipoprotein and eliciting local inflammation. Previously, we and others have shown C1q/TNF-related proteins (CTRPs) play diverse roles in vascular functions. In this study, we sought to investigate the changes in CTRP expression levels during vital biological processes in macrophages and their relation to inflammatory responses. METHODS: Western blot and real-time PCR were performed to analyze CTRPs expression levels in human peripheral blood mononuclear cells, primary macrophages and lipid-laden foam cells. Mechanisms that regulate CTPR1 expression were further investigated by bioinformatic analysis and chromatin immunoprecipitation. Enzyme-linked immunosorbent assay was performed to measure the concentration of inflammatory cytokines. RESULTS: We found that almost all CTRPs were significantly increased in primary human macrophages after differentiation from peripheral blood mononuclear cells. In particular, CTRP1 was further up-regulated upon exposure to oxidized low-density lipoprotein (oxLDL) in a peroxisome proliferator-activated receptor (PPAR)-dependent manner. Chromatin immunoprecipitation also confirmed the presence of PPAR-γ in the CTRP1 promoter after oxLDL treatment. Stimulation of CTRP1 led to markedly enhanced secretion of pro-atherogenic factors, including MCP-1, TNF-α, IL-1ß, and IL-6, whereas oxLDL-induced inflammatory cytokine production was significantly attenuated after the treatment with CTRP1 neutralizing antibody. CONCLUSIONS: These data suggest an essential role of CTRP1 in linking dysregulation of lipid metabolism and inflammatory responses in macrophages.
Assuntos
Aterosclerose/metabolismo , Regulação da Expressão Gênica , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Proteínas/metabolismo , Anticorpos Neutralizantes/metabolismo , Citocinas/metabolismo , Citometria de Fluxo , Células Espumosas/metabolismo , Humanos , Inflamação , Leucócitos Mononucleares/citologia , Lipoproteínas LDL/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de SinaisRESUMO
BACKGROUND: We investigated whether serum vasostatin-2 level is related to chronic heart failure (CHF) in patients with previous myocardial infarction (MI) and MACE in 3-year follow-up. The biological effect of vasostatin-2 on ischemic HF was evaluated in animal experiments. METHODS: After exclusion of the subjects not eligible, this study included 450 patients with CHF and previous MI, and 149 healthy controls. Serum vasostatin-2 level was analyzed. CHF patients were followed up for three years and major adverse cardiac events (MACE) were recorded, defined as reinfarction, target-vessel revascularization, cardiovascular death and refractory HF requiring hospitalizations. RESULTS: Notably, serum vasostatin-2 level was decreased in CHF patients than in controls, and significant difference was observed between CHF patients with MACE and those without (both P<0.05). Vasostatin-2 level was correlated with HF stages (Spearman's r=-0.288, P<0.05), LVEF (r=0.377, P<0.05) and pro-BNP level (r=-0.294, P<0.05). Multivariable logistic regression analysis suggested that vasostatin-2, conventional risk factors, severity of HF stages and LVEF were independently associated with MACE in CHF patients. Vasostatin-2 (100µg) or PBS was injected intraperitoneally every other day in MI rats, follow by echocardiography, hemodynamic analysis after 2months. Compared with PBS, vasostatin-2 treatment prevented ischemic HF in MI rats, accompanied with reduction of infarct size, remodeling, fibrosis and inflammation, mainly through inhibition of Rho, Wnt and TLR-4 pathways and modulation of renin-angiotensin system. CONCLUSION: Decreased serum vasostatin-2 level is associated with ischemic CHF and with MACE in three-year follow-up. Intraperitoneal injection of vasostatin-2 protects against ischemic HF in MI rats.
Assuntos
Cromogranina A , Fibrose/prevenção & controle , Insuficiência Cardíaca , Inflamação/prevenção & controle , Infarto do Miocárdio , Isquemia Miocárdica , Fragmentos de Peptídeos , Idoso , Animais , China/epidemiologia , Cromogranina A/análise , Cromogranina A/sangue , Modelos Animais de Doenças , Ecocardiografia/métodos , Feminino , Fibrose/metabolismo , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Isquemia Miocárdica/sangue , Isquemia Miocárdica/prevenção & controle , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/sangue , Fatores de Proteção , RatosRESUMO
Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-ß (IL1-ß), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4-/-). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4-/- primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation.