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1.
Cell Death Dis ; 11(2): 97, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029701

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Cell Death Dis ; 11(1): 22, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924749

RESUMO

Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.

3.
PLoS One ; 14(8): e0220654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31369621

RESUMO

BACKGROUND/AIM: No-reflow is a serious and frequent event during primary percutaneous coronary intervention (PPCI) for acute ST segment elevation myocardial infarction (STEMI). The aim of this study was to identify possible predictors for no-reflow. PATIENTS AND METHODS: We investigated 218 patients with acute anterior STEMI who underwent PPCI from December 2016 to December 2018. No-reflow was defined as a coronary TIMI flow grade of ≤ 2. TIMI flow grade 3 was defined as normal reflow. RESULTS: In our study, the no-reflow phenomenon was observed in 39 patients (18%) during angiography. The patients of no-reflow group were found to be more older, diabetics, longer pain-to-balloon time, lower blood pressure, higher platelet counts and higher levels of D-Dimer and Cystatin C (Cys-C). In multivariate logistic regression analysis, only diabetes (OR = 0.371, 95% CI: 0.157-0.872, P = 0.023), longer pain-to-balloon time (OR = 1.147, 95% CI: 1.015-1.297, P = 0.028) and higher Cys-C level (OR = 10.07, 95% CI: 2.340-43.377, P = 0.002) were predictors for no-reflow. CONCLUSION: Cys-C might be a useful predictor for the no-reflow phenomenon after PPCI in STEMI patients. It might help to screen STEMI patients with high risk of no-reflow on admission.

4.
Perfusion ; 34(1): 15-21, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30004298

RESUMO

BACKGROUND/AIM:\: Rho kinase is a downstream effector of Rho GTPase that is known to regulate various pathological processes. The aim of this study was to evaluate the regulation of Rho kinase activity in leukocytes in patients with ischemia/reperfusion (I/R) injury. PATIENTS AND METHODS: We investigated 38 patients with acute ST-segment elevation myocardial infarction (STEMI), 26 patients with atherosclerosis (AS) and 22 normal subjects. All patients underwent coronary angiography (CAG) and all STEMI patients received primary percutaneous coronary intervention (PPCI) of the left anterior descending artery (LAD) within 12 h after chest pain on-set. Blood samples for leukocyte Rho kinase activity were obtained before CAG and 3 and 24 hours after CAG/PCI. RESULTS: Rho kinase activity increased in the I/R and AS groups. Compared with the AS group, Rho kinase activity was significantly higher in peripheral blood leukocytes in STEMI/PPCI. Furthermore, there was no correlation between changes in Rho kinase activity and changes in high-sensitivity troponin I (hs-TnI) and C-reactive protein (CRP). There was a negative correlation between Rho kinase activity and IL-6. CONCLUSION: Rho kinase is involved in the pathogenesis of heart I/R injury in patients. Inhibition of Rho kinase may be an additional therapeutic intervention for the treatment of I/R.


Assuntos
Biomarcadores/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/enzimologia , Quinases Associadas a rho/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Troponina I/metabolismo
5.
J Int Med Res ; 47(1): 152-158, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30208754

RESUMO

OBJECTIVE: To determine if high fasting blood glucose (FBG) level is an independent predictor of serious coronary lesions in patients with coronary artery disease (CAD). METHODS: We enrolled 64 patients who had symptoms of chest discomfort and who underwent coronary angiography. FBG was determined from blood samples and the extent of coronary artery lesions was analyzed according to Gensini score. We examined the relationships among diabetes, FBG, and coronary artery severity. RESULTS: Diabetes and FBG were significantly and positively related to Gensini score. Diabetes, but not FBG, was independently correlated with the occurrence of a Gensini score >41. However, FBG was significantly associated with Gensini score >41 in non-diabetic patients. CONCLUSION: Hyperglycemia is an independent predictor of severe CAD in non-diabetic patients. Clinicians should be aware of this and should carry out appropriate early interventions.


Assuntos
Glicemia/metabolismo , Doença da Artéria Coronariana/diagnóstico , Hiperglicemia/diagnóstico , Fatores Etários , Idoso , Biomarcadores/sangue , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/fisiopatologia , Estudos Transversais , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Jejum/sangue , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Fatores Sexuais
6.
BMJ Open ; 8(3): e020019, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29511018

RESUMO

INTRODUCTION: Provisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs. METHODS AND ANALYSIS: This DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two-stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis. ETHICS AND DISSEMINATION: The study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT02284750; Pre-results.


Assuntos
Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/cirurgia , Estenose Coronária/terapia , Vasos Coronários/cirurgia , Stents , Idoso , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Stents Farmacológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Desenho de Prótese , Projetos de Pesquisa , Resultado do Tratamento
7.
J Cell Mol Med ; 22(2): 808-822, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29063670

RESUMO

Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes-induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r-irisin (low or high dose: 0.5 or 1.5 µg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low-dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high-dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low-dose irisin involved irisin-mediated inhibition of high glucose-induced endothelial-to-mesenchymal transition (EndMT); conversely, high-dose irisin treatment enhanced high glucose-induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low-dose irisin alleviated DCM development by inhibiting high glucose-induced EndMT. By contrast, high-dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose-induced EndMT and exert a dose-dependent bidirectional effect on DCM.


Assuntos
Cardiomiopatias Diabéticas/patologia , Fibronectinas/farmacologia , Glucose/toxicidade , Células Endoteliais da Veia Umbilical Humana/patologia , Mesoderma/patologia , Animais , Glicemia/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mesoderma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Exp Ther Med ; 14(3): 2497-2504, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28962186

RESUMO

Ulinastatin exhibits anti-inflammatory activity and protects the heart from ischemia/reperfusion injury. However, whether ulinastatin has a protective effect in diabetic cardiomyopathy is yet to be elucidated. The aim of the present study was to investigate the protective effects of ulinastatin against diabetic cardiomyopathy and its underlying mechanisms. A C57/BL6J mice model of diabetic cardiomyopathy was used and mice were randomly assigned to three groups: Control group, diabetes mellitus (DM) group and DM + ulinastatin treatment group. Cardiac function was assessed using echocardiography and the level of inflammatory cytokine high mobility group box 1 (HMGB1) expression was measured using histopathological examination and reverse transcription-quantitative polymerase chain reaction. The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured using western blotting and ELISA. The apoptosis rate in the myocardium was assessed by TUNEL assay. Caspase-3 activation, expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated × (Bax) were measured using western blotting, as was the activity of the mitogen activated protein kinase (MAPK) signaling pathway. The results indicated that ulinastatin significantly improved cardiac function in mice with DM. Ulinastatin treatment significantly downregulated HMGB1, TNF-α and IL-6 expression (P<0.05) and significantly reduced the percentage of apoptotic cardiomyocytes (P<0.05) via reduction of caspase-3 activation and the ratio of Bax/Bcl-2 in diabetic hearts (P<0.05). In addition, ulinastatin attenuated the activation of the MAPK signaling pathway. In conclusion, ulinastatin had a protective effect against DM-induced cardiac dysfunction in a mouse model. This protective effect may be associated with the anti-inflammatory and anti-apoptotic abilities of ulinastatin via the MAPK signaling pathway.

9.
Mol Med Rep ; 14(1): 649-54, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27221044

RESUMO

The aim of the present study was to identify the genetic defect responsible for familial coronary artery disease/myocardial infarction (CAD/MI), which exhibited an autosomal dominant pattern of inheritance, in an extended Chinese Han pedigree containing 34 members. Using exome and Sanger sequencing, a novel 6­base pair (bp) 'CAGCCG' deletion in exon 11 of the myocyte enhancer factor 2A (MEF2A) gene was identified, which cosegregated with CAD/MI cases in this family. This 6­bp deletion was not detected in 311 sporadic cases of premature CAD/MI or in 323 unrelated healthy controls. Determination of a genetic risk profile has a key role in understanding the pathogenesis of CAD and MI. Among the reported risk­conferring genes and their variants, mutations in MEF2A have been reported to segregate with CAD/MI in Caucasian families. Causative missense mutations have also been detected in sporadic CAD/MI cases. However, this suggested genetic linkage is controversial, since it could not be confirmed by ensuing studies. The discovery of a novel MEF2A mutation in a Chinese family with premature CAD/MI suggests that MEF2A may have a significant role in the pathogenesis of premature CAD/MI. To better understand this association, further in vitro and in vivo studies are required.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Fatores de Transcrição MEF2/genética , Deleção de Sequência , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Grupo com Ancestrais do Continente Asiático , Biomarcadores , Criança , China , Mapeamento Cromossômico , Angiografia Coronária , Exoma , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
10.
Oncotarget ; 7(21): 31053-66, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27105518

RESUMO

Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.


Assuntos
Diabetes Mellitus Experimental/terapia , Fibrose/terapia , Fatores de Transcrição MEF2/antagonistas & inibidores , Miocárdio/patologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Transição Epitelial-Mesenquimal , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores de Transcrição MEF2/biossíntese , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Transdução de Sinais , Transfecção
11.
Yonsei Med J ; 57(2): 321-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26847282

RESUMO

PURPOSE: Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis. MATERIALS AND METHODS: Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg·kg⁻¹·d⁻¹) and high-dose darapladib (50 mg·kg⁻¹·d⁻¹) interventions were then administered over the course of 2 weeks. RESULTS: The serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05). CONCLUSION: Darapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Benzaldeídos , Oximas , Inibidores de Fosfolipase A2/administração & dosagem , Quinases Associadas a rho/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase/efeitos dos fármacos , Animais , Aterosclerose/sangue , Proteína C-Reativa/metabolismo , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Masculino , Inibidores de Fosfolipase A2/efeitos adversos , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue
12.
Oncotarget ; 7(1): 66-80, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26623724

RESUMO

Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions including proliferation, apoptosis, tumor suppression, transcription, and mitochondrial protein folding. However, its function in diabetic cardiomyopathy (DCM) is still unclear. In vivo, type 2 diabetic rat model was induced by using a high-fat diet and low-dose streptozotocin. Overexpression of the PHB protein in the model rats was achieved by injecting lentivirus carrying PHB cDNA via the jugular vein. Characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Rats with DCM showed severe insulin resistance, left ventricular dysfunction, fibrosis and apoptosis. PHB overexpression ameliorated the disease. Cardiofibroblasts (CFs) and H9c2 cardiomyoblasts were used in vitro to investigate the mechanism of PHB in altered function. In CFs treated with HG, PHB overexpression decreased expression of collagen, matrix metalloproteinase activity, and proliferation. In H9c2 cardiomyoblasts, PHB overexpression inhibited apoptosis induced by HG. Furthermore, the increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was significantly decreased and the inhibited phosphorylation of Akt was restored in DCM. Therefore, PHB may be a new therapeutic target for human DCM.


Assuntos
Cardiomiopatias/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Miocárdio/metabolismo , Proteínas Repressoras/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Western Blotting , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose/genética , Expressão Gênica , Testes de Função Cardíaca , Humanos , Resistência à Insulina/genética , Masculino , Microscopia de Fluorescência , Miocárdio/patologia , Fosforilação , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Disfunção Ventricular Esquerda/genética
13.
Clin Exp Pharmacol Physiol ; 42(12): 1266-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26331430

RESUMO

Age-related endothelial dysfunction is closely associated with the local production of reactive oxygen species (ROS) within and in the vicinity of the vascular endothelium. Oxidant-induced DNA damage can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), leading to endothelial dysfunction in various pathophysiological conditions. The present study aimed to investigate the role of PARP-1 in age-dependent changes in endothelial cell function and its underlying mechanism. Wild-type (WT) and PARP-1(-/-) mice were divided into young (2 months) and old (12 months) groups. Isolated aortic rings were suspended to record isometric tension to assess endothelial function. Nitric oxide (NO) production and content in plasma were detected by spectrophotometry. Superoxide (O2(-) production was detected by dihydroethidium. Expression of PARP-1, endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS), and arginase-2 (Arg2) was assessed by western blot analysis. Endothelium-dependent relaxation in response to acetylcholine was lost in old WT, but not PARP-1(-/-), mice. Endothelium-independent vasodilation was not impaired in aging mice. Production of O2(-) was greater in aging WT mice than young or aging PARP-1(-/-) mice. eNOS expression was not affected by aging in WT or PARP-1(-/-) mice, but p-eNOS expression decreased and iNOS and Arg2 levels were upregulated only in aging WT mice. In conclusion, PARP-1 inhibition may protect against age-dependent endothelial dysfunction, potentially by regulating NO bioavailability via iNOS. Inhibition of PARP-1 may help in vascular aging prevention.


Assuntos
Envelhecimento/metabolismo , Endotélio Vascular/enzimologia , Deleção de Genes , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Angiotensina II/farmacologia , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nitrilos/farmacologia , Poli(ADP-Ribose) Polimerase-1/deficiência , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonas/farmacologia , Superóxidos/metabolismo
14.
Postgrad Med ; 127(5): 446-54, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25927862

RESUMO

OBJECTIVE: Krüppel-like factor 2 (KLF2) is a transcription factor that regulates endothelial function and atorvastatin can stabilize atherosclerotic plaque and inhibit inflammation on endothelial cells by attenuating the role of cytokines. The aim of this study is to investigate the effect of high glucose (HG) on KLF2 expression in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms. METHODS: HUVECs were isolated from the human umbilical cords from normal pregnancies and exposed to medium containing 25.5 mM D-glucose for 24 hours as the HG induction model (HG group). In the HG plus atorvastatin groups or KLF2 gene transduction, the medium then was collected for the nitric oxide (NO) assay and the cells were harvested for Western blot and for the real-time polymerase chain reaction to observe the expression of KLF2, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, total and phosphorylated endothelial NO synthase (eNOS), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, caspase-3 and cleaved caspase-3 and the role of the p38MAPK and ERK1/2 intracellular signal pathway. The cells' apoptosis was analyzed by flow cytometry. RESULTS: HG dose-dependently increased apoptosis. The presence of HG inhibited the expression of KLF2 mRNA and protein in HUVECs and atorvastatin treatment increased KLF2 expression, thus counteracted HG-induced suppression of KLF2 expression, and overexpression of KLF2 might protect the cells from apoptosis. HG increased the expression of VCAM-1, ICAM-1, but decreased the nitric oxide release and the expression of p-eNOs/eNos in HUVECs. However, atorvastatin reversed these changes and also attenuated high-glucose induced p38 MAPK and ERK1/2 phosphorylation. CONCLUSIONS: HG suppressed the KLF2 expression in HUVECs. The suppression was counteracted by atorvastatin treatment, probably via attenuating the activation of the signal pathyway p38 MAPK and ERK1/2.


Assuntos
Glucose/farmacologia , Ácidos Heptanoicos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , Pirróis/farmacologia , Atorvastatina , Técnicas de Cultura de Células , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
15.
Pharmazie ; 70(1): 24-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25975094

RESUMO

In this study, we aimed to detect the effects of the soluble epoxide hydrolase (sEH) inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) on atherosclerotic diseases and to explore its mechanism. The atherosclerosis animal model was constructed by ApoE-/- mice. To determine the optimal therapeutic concentration of AUDA, different concentrations of AUDA were infused into ApoE-/- mice, with controls receiving infusions of normal saline alone. Mouse body weight and serum total cholesterol, triglyceride, LDL and HDL levels were measured. The western blotting (WB) method was used to detect the expression of TLR4 and NFKB in the aortic wall of the AUDA-treated and control mice. After the animals were sacrificed, we performed Oil Red O staining of the aortic sinus atherosclerotic plaque area followed by quantitative analysis of the aortic atherosclerotic plaque size and the percentage of lumen area in the two groups of mice. The expression levels of inflammatory cytokines, adhesion molecules and chemokines in the AUDA group were significantly decreased compared to the saline-treatment group (P < 0.05). The optimal AUDA concentration was found to be 0.35 ml/mg. AUDA significantly inhibited the expression of TLR4 and NFκB in ApoE-/- mouse aortas and reduced the aortic sinus plaque area of the ApoE-/- mouse group (P < 0.05). In conclusion, AUDA can regulate blood lipid balance, which may be one of the mechanisms for its protective effects on the cardiovascular system.


Assuntos
Adamantano/análogos & derivados , Aterosclerose/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Láuricos/uso terapêutico , Adamantano/uso terapêutico , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Citocinas/biossíntese , Técnicas In Vitro , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Receptor 4 Toll-Like/metabolismo
16.
Postgrad Med ; 127(2): 144-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25539718

RESUMO

OBJECTIVE: Hypoxia inducible factor-1α (HIF-1α) regulates many genes involved in angiogenesis during embryonic development. Epidermal growth factor-like domain 7 (Egfl7) is a specific marker for human arterial endothelial cells that are in an activated state of proliferation, migration, and remodeling. This study evaluates the intricate relationship between HIF-1α and Egfl7 under both hyperoxia and hypoxia states. METHODS: The neonatal mice were exposed to either hyperoxia or hypoxia in order to detect the pulmonary and cardiac Egfl7 messenger RNA (mRNA) or protein expression regulated by oxygen tension in vivo by reverse transcriptase polymerase chain reaction or immunohistochemistry staining. Egfl7 expression in HIF-1α null pulmonary endothelial cells in hypoxia conditions and effects of overexpression or knockdown of HIF-1α on Egfl7 expression in human umbilical vein endothelial cells would be clarified in vitro by reverse transcriptase polymerase chain reaction and Western blot, respectively. RESULTS: Hyperoxia exposure significantly reduced Egfl7 expression in neonatal mice lungs by 36% compared with age-matched normoxia control mice (P < 0.05, n = 6). The pulmonary Egfl7 transcription levels were increased by 1.7- and 1.9-fold in 24 hours and by day 8 in hypoxia groups compared with the normoxia control values (P < 0.05, n = 6). The cardiac Egfl7 mRNA expression was significantly increased by 4.5-fold in the day 8 group compared with the normoxia control values (P < 0.05, n = 6). The expression of Egfl7 decreased significantly in the HIF-1α(-/-) endothelial cells (ECs), which was only 26% of wild-type HIF-1α(+/+) ECs (P < 0.05, n = 3). Hypoxia caused a mild but significant increase of Egfl7 expression in HIF-1α(+/+) ECs (P < 0.05). In vitro, overexpression of HIF-1α enhanced Egfl7 expression, whereas knockdown of HIF-1α reduced Egfl7 expression. CONCLUSIONS: Overexpression of HIF-1α enhanced Egfl7 expression, whereas knockdown of HIF-1α reduced Egfl7 expression. Egfl7 could be a HIF-1α responsive gene regulated by oxygen tension.


Assuntos
Regulação da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Proteínas/metabolismo , Animais , Animais Recém-Nascidos , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Hiperóxia/metabolismo , Hipóxia/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos
17.
J Cell Mol Med ; 18(11): 2311-20, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25210949

RESUMO

Apoptosis is a key event involved in diabetic cardiomyopathy. The expression of high mobility group box 1 protein (HMGB1) is up-regulated in diabetic mice. However, the molecular mechanism of high glucose (HG)-induced cardiomyocyte apoptosis remains obscure. We aimed to determine the role of HMGB1 in HG-induced apoptosis of cardiomyocytes. Treating neonatal primary cardiomyocytes with HG increased cell apoptosis, which was accompanied by elevated levels of HMGB1. Inhibition of HMGB1 by short-hairpin RNA significantly decreased HG-induced cell apoptosis by reducing caspase-3 activation and ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2). Furthermore, HG activated E26 transformation-specific sequence-1 (Ets-1), and HMGB1 inhibition attenuated HG-induced activation of Ets-1 via extracellular signal-regulated kinase 1/2 (ERK1/2) signalling. In addition, inhibition of Ets-1 significantly decreased HG-induced cardiomyocyte apoptosis. Similar results were observed in streptozotocin-treated diabetic mice. Inhibition of HMGB1 by short-hairpin RNA markedly decreased myocardial cell apoptosis and activation of ERK and Ets-1 in diabetic mice. In conclusion, inhibition of HMGB1 may protect against hyperglycaemia-induced cardiomyocyte apoptosis by down-regulating ERK-dependent activation of Ets-1.


Assuntos
Apoptose/genética , Diabetes Mellitus Experimental/genética , Cardiomiopatias Diabéticas/genética , Proteína HMGB1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Animais , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/patologia , Proteína HMGB1/antagonistas & inibidores , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Camundongos , Camundongos Endogâmicos NOD , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Transdução de Sinais/genética , Proteína X Associada a bcl-2/genética
18.
Mol Biol Rep ; 41(9): 6225-31, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24981928

RESUMO

This study aimed to evaluate the role of cystatin C (CysC) in the vascular remodeling of balloon-injured abdominal aorta of rabbits. Forty-eight New Zealand white rabbits were randomly divided into three groups: the balloon-injured injury group (n = 16), the CysC monoclonal antibody group (n = 16), and the sham-operative group (n = 16). Serum CysC levels were detected by enzyme linked immunosorbent assay. Changes in adventitial area, adventitial thickness, lumen area (LA), neointimal area (IA), internal elastic lamina area (IELA), external elastic lamina area (EELA), vascular remodeling index (VRI) and residual stenosis (RS) were measured by the Leica image analysis system. Immunohistochemical analysis of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were performed. Serum CysC levels of rabbits in the balloon-injured injury group were significantly higher than those in the CysC monoclonal antibody group and the sham-operative group (both P < 0.05). At 6 weeks after balloon injury, the adventitial area and thickness, LA, IA, IELA and EELA in the balloon-injured injury group were also higher than those in the CysC monoclonal antibody and sham-operative groups (all P < 0.05). In addition, the balloon-injured injury group showed higher VRI and RS than those of the CysC monoclonal antibody group (both P < 0.05). The positive expression of α-SMA in the vascular adventitia and media in the balloon-injured group were higher than that of the CysC monoclonal antibody and sham-operative groups. The balloon-injured group also showed a stronger expression of α-SMA in the neointima than that of the CysC monoclonal antibody group. There was a strong positive expression of PCNA in the vascular adventitia and neointima in the balloon-injured and CysC monoclonal antibody groups. However, the number of PCNA-positive cells in the balloon-injured group was higher than that of the CysC monoclonal antibody group (25.45 ± 4.21 vs. 6.75 ± 1.11, P = 0.003). Our findings provide empirical evidence that serum CysC levels may play an important role in the vascular remodeling of balloon-injured abdominal aorta of rabbits.

19.
Int J Cardiol ; 172(1): 202-12, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24485636

RESUMO

BACKGROUND: High-mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. Its expression is increased in diabetic cardiomyopathy (DCM), but its role is unclear. We investigated the potential role and mechanism of HMGB1 in diabetes-induced myocardial fibrosis and dysfunction in mice. METHODS: In vivo, type 1 diabetes was induced by streptozotocin (STZ) in mice. HMGB1 expression was knocked down by lentivirus-mediated short-hairpin RNA (shRNA). Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. HMGB1, collagen I and III, and transforming growth factor ß1 (TGF-ß1) expression was quantified by immunostaining and western bolt analysis. In vitro, isolated neonatal cardiac fibroblasts were treated with high glucose (HG) or recombinant HMGB1 (rHMGB1). Pharmacologic (neutralizing anti-HMGB1 antibody) or genetic (shRNA-HMGB1) inhibition of HMGB1 was used to investigate the role of HMGB1 in HG-induced functional changes of cardiac fibroblasts. RESULTS: In vivo, HMGB1 was diffusely expressed in the myocardium of diabetic mice. HMGB1 silencing ameliorated left ventricular dysfunction and remodeling and decreased collagen deposition in diabetic mice. In vitro, HG induced HMGB1 translocation and secretion in both viable cardiomyocytes and fibroblasts. Administration of rHMGB1 dose-dependently increased the expression of collagens I and III and TGF-ß1 in cardiac fibroblasts. HMGB1 inhibition reduced HG-induced collagen production, matrix metalloproteinase (MMP) activities, proliferation, and activated mitogen-activated protein kinase signaling in cardiac fibroblasts. CONCLUSIONS: HMGB1 inhibition could alleviate cardiac fibrosis and remodeling in diabetic cardiomyopathy. Inhibition of HMGB1 might have therapeutic potential in the treatment of the disease.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Cardiomiopatias Diabéticas/imunologia , Proteína HMGB1/genética , Proteína HMGB1/imunologia , Animais , Técnicas de Cultura de Células , Movimento Celular , Proliferação de Células , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Fibrose/diagnóstico por imagem , Fibrose/imunologia , Fibrose/metabolismo , Proteína HMGB1/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Miocárdio/imunologia , Miócitos Cardíacos/imunologia , RNA Interferente Pequeno/genética , Transdução de Sinais/imunologia
20.
Mol Biol Rep ; 41(5): 3021-31, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24458828

RESUMO

This meta-analysis of case-control studies was conducted to determine whether SELE genetic polymorphisms contribute to the pathogenesis of coronary heart disease (CHD) and myocardial infarction (MI). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Twenty case-control studies met the inclusion criteria, with a total of 2,292 CHD patients, 901 MI patients and 3,233 healthy controls. Six common polymorphisms in the SELE gene were evaluated, including 554L/F, 98G/T, 128S/R, 2692G/A, 1901C/T, and 1856A/G. The results of our meta-analysis suggest that SELE genetic polymorphisms might be strongly correlated with an increased risk of CHD (allele model: OR 2.08, 95% CI 1.67-2.58, P<0.001; dominant model: OR 2.12, 95% CI 1.68-2.68, P<0.001; respectively), especially the SELE 554L/F, 98G/T and 128S/R polymorphisms. Furthermore, our findings indicated that SELE genetic polymorphisms were closely linked to the risk of CHD in Asians but not Caucasians. However, our findings reveal no positive correlations between SELE genetic polymorphisms and MI risk (allele model: OR 1.39, 95% CI 1.00-1.94, P=0.054; dominant model: OR 1.40, 95% CI 0.96-2.04, P=0.081; respectively). The current meta-analysis suggests that SELE genetic polymorphisms may contribute to an increased risk of CHD, especially the SELE 554L/F, 98G/T and 128S/R polymorphisms in Asians. However, SELE genetic polymorphisms may not be important determinants of susceptibility to MI.


Assuntos
Doença das Coronárias/genética , Selectina E/genética , Predisposição Genética para Doença , Infarto do Miocárdio/genética , Polimorfismo Genético , Alelos , Estudos de Casos e Controles , Genótipo , Humanos , Razão de Chances , Viés de Publicação
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