RESUMEN
BACKGROUND: The present study was aimed to establish a prediction model for in-stent restenosis (ISR) in subjects who had undergone percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). MATERIALS AND METHODS: A retrospective cohort study was conducted. From September 2010 to September 2013, we included 968 subjects who had received coronary follow-up angiography after primary PCI. The logistic regression analysis, receiver operator characteristic (ROC) analysis, nomogram analysis, Hosmer-Lemeshow χ2 statistic, and calibration curve were applied to build and evaluate the prediction model. RESULTS: Fifty-six patients (5.79%) occurred ISR. The platelet distribution width (PDW), total cholesterol (TC), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and lesion vessels had significant differences between ISR and non-ISR groups (all P < 0.05). And these variables were independently associated with ISR (all P < 0.05). Furthermore, they were identified as predictors (all AUC > 0.5 and P < 0.05) to establish a prediction model. The prediction model showed a good value of area under curve (AUC) (95%CI): 0.72 (0.64-0.80), and its optimized cut-off was 6.39 with 71% sensitivity and 65% specificity to predict ISR. CONCLUSION: The incidence of ISR is 5.79% in CAD patients with DES implantation in the Xinjiang population, China. The prediction model based on PDW, SBP, TC, LDL-C, and lesion vessels was an effective model to predict ISR in CAD patients with DESs implantation.
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Plaquetas/metabolismo , Enfermedad de la Arteria Coronaria/sangre , Stents Liberadores de Fármacos/efectos adversos , Lípidos/sangre , Anciano , Angiografía/métodos , Calibración , Enfermedad de la Arteria Coronaria/diagnóstico , Reestenosis Coronaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Análisis Multivariante , Nomogramas , Curva ROC , Análisis de Regresión , Estudios Retrospectivos , RiesgoRESUMEN
BACKGROUND: FBXW7 gene expression is positively correlated with glycolipid metabolism and is associated with diabetes in animal models. In the current study, we focused on exploring whether genetic variants of the FBXW7 gene were associated with type 2 diabetes (T2DM) and the risk factors for T2DM in Uygur people in Xinjiang, China. METHODS: A total of 2164 Chinese Uygur subjects (673 T2DM patients and 1491 controls) were recruited for our case-control study, and four SNPs (rs10033601, rs2255137, rs2292743 and rs35311955) of the FBXW7 gene were genotyped using the improved multiplex ligation detection reaction (iMLDR) technique. RESULTS: Our study showed that the genotypes using the overdominant model (GA vs AA + GG) of rs10033601 and using the overdominant model (TA vs TT + AA) of rs2292743 were significantly different between T2DM patients and the controls (P = 0.005 and P = 0.012, respectively). After multivariate adjustments for confounders, the rs10033601 and rs2292743 SNPs were still independent risk factors for T2DM [GA vs AA + GG: odds ratio = 1.35, 95% confidence interval (CI) = 1.12-1.64, P = 0.002; TA vs TT + AA: OR = 1.28, 95% CI = 1.06-1.55, P = 0.011]. Participants within the Chinese Uygur populations and who with the GA genotype of rs10033601 and the TA genotype of rs2292743 were associated with significantly elevated glucose levels. CONCLUSIONS: Our study revealed that both rs10033601 and rs2292743 of the FBXW7 gene were associated with T2DM in the Uygur populations in Xinjiang.
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Diabetes Mellitus Tipo 2/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Anciano , Estudios de Casos y Controles , China/epidemiología , Diabetes Mellitus Tipo 2/etnología , Etnicidad , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
PURPOSE: We investigated whether increased expression of activated mitogen-activated protein kinase (MAPK) kinases 1 (MEK1) restores ischemic post-conditioning (IPostC) protection in hypertrophic myocardium following ischemia/reperfusion (I/R) injury. METHODS: C57Bl/6 mice received recombinant adeno-associated virus type 9 (rAAV9)-mediated activated MEK1 gene delivery systemically, then following the induction of cardiac hypertrophy via transverse aortic constriction for 4 weeks. In a Langendorff model, hypertrophic hearts were subjected to 40 min/60 min I/R or with IPostC intervention consisting of 6 cycles of 10 s reperfusion and 10 s no-flow before a 60-min reperfusion. Hemodynamics, infarct size (IS), myocyte apoptosis and changes in expression of reperfusion injury salvage kinase (RISK) pathway were examined. RESULTS: rAAV9-MEK1 gene delivery led to a 4.3-fold and 2.7-fold increase in MEK1 mRNA and protein expression in the heart versus their control values. I/R resulted in a larger IS in hypertrophic than in non-hypertrophic hearts (52.3 ± 4.7% vs. 40.0 ± 2.5%, P < 0.05). IPostC mediated IS reduction in non-hypertrophic hearts (27.6 ± 2.6%, P < 0.05), while it had no significant effect in hypertrophic hearts (46.5 ± 3.1%, P=NS) compared with the IS in non-hypertrophic or hypertrophic hearts subjected to I/R injury only, respectively. Hemodynamic decline induced by I/R was preserved by IPostC in non-hypertrophic hearts but not in hypertrophic hearts. rAAV9-MEK1 gene delivery restored IPostC protection in hypertrophic hearts evidenced by reduced IS (32.0 ± 2.8% vs. 46.5 ± 3.1%) and cardiac cell apoptosis and largely preserved hemodynamic parameters. These protective effects were associated with significantly increased phosphorylation of ERK1/2 and ribosomal protein S6 kinases (p70S6K), but it had no influence on Akt and glycogen synthase kinase-3ß. CONCLUSION: These results demonstrated that rAAV9-mediated activated MEK1 expression restores IPostC protection in the hypertrophic heart against I/R injury through the activation of ERK pathway.
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Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos , Hipertrofia Ventricular Izquierda/terapia , Poscondicionamiento Isquémico , MAP Quinasa Quinasa 1/biosíntesis , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/enzimología , Animales , Apoptosis , Modelos Animales de Enfermedad , Inducción Enzimática , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Preparación de Corazón Aislado , MAP Quinasa Quinasa 1/genética , Masculino , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Infarto del Miocardio/enzimología , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Fosforilación , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismoRESUMEN
BACKGROUND: Inflammation and oxidative stress play predominant roles in the initiation and progression of ischaemia/reperfusion (I/R) injury, with nuclear factor kappa B (NF-κB) serving as a crucial mediator. Overexpression of the inhibitor of κB alpha (IκBα) gene is hypothesized to have protective effects against apoptosis and autophagy in cardiomyocytes subjected to hydrogen peroxide (H2O2) by inhibiting the NF-κB pathway. METHODS: The IκBαS32A, S36A gene was transfected via adeno-associated virus serotype 9 (AAV9) delivery into neonatal rat ventricular cardiomyocytes (NRVMs) prior to H2O2 treatment. NRVMs were divided into control, H2O2, GFP + H2O2, IκBα+H2O2, and pyrrolidine dithiocarbamate (PDTC) + H2O2 groups. Nuclear translocation of the NF-κB p65 subunit was evaluated by immunofluorescence and Western blotting. Cell viability was assessed by Cell Counting Kit-8 assay. Supernatant lactate dehydrogenase (LDH) and intracellular malondialdehyde (MDA) were measured to identify H2O2-stimulated cytotoxicity. Apoptosis was determined by Annexin V-PE/7-AAD staining, and the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining. Western blotting was used to detect apoptosis- and autophagy-related proteins. RESULTS: IκBα transfection significantly increased cell viability and ΔΨm but decreased the supernatant LDH and cellular MDA levels in cardiomyocytes exposed to H2O2. Meanwhile, IκBα overexpression decreased H2O2-induced apoptosis by upregulating the Bcl-2/Bax ratio and reduced autophagy by downregulating the expression of Beclin-1 and the LC3-II/LC3-I ratio. These effects partly accounted for the ability of IκBα to inhibit the NF-κB signalling pathway, as evidenced by decreases in p65 phosphorylation and nuclear translocation. Indeed, the effects of inactivation of NF-κB signalling with the specific inhibitor PDTC resembled the cardioprotective effects of IκBα during H2O2 stimulation. CONCLUSION: IκBα overexpression can ameliorate H2O2-induced apoptosis, autophagy, oxidative injury, and ΔΨm loss through inhibition of the NF-κB signalling pathway. These findings suggest that IκBα transfection can result in successful resistance to oxidative stress-induced damage by inhibiting NF-κB activation, which may provide a potential therapeutic target for the prevention of myocardial I/R injury.
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Peróxido de Hidrógeno/farmacología , Miocitos Cardíacos/patología , Inhibidor NF-kappaB alfa/genética , FN-kappa B/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Autofagia/efectos de los fármacos , Autofagia/genética , Células Cultivadas , Dependovirus/genética , Regulación de la Expresión Génica , Peróxido de Hidrógeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Pirrolidinas/farmacología , Ratas Sprague-Dawley , Tiocarbamatos/farmacología , TransfecciónRESUMEN
We investigate the association of uric acid with hypertension among Han, Uygur, and Kazakh populations in the Xinjiang Province of Western China. Our study aims to evaluate the relationships of serum uric acid (SUA) with hypertension in the Chinese population according to the menopausal status. Medical data of 1684 Han, 1895 Uygur, and 294 Kazakh people was examined. The prevalence of hypertension was calculated by the quartiles of SUA. Correlation between hypertension-related risk factors calculated and compared between men and women. SUA was higher in men than in women. The level was significantly higher in postmenopausal than premenopausal women (4.40 ± 1.75 v.s 4.06 ± 1.63 mg/dl, P < .01). Logistic regression analysis showed Body mass index (BMI) [OR = 1.08, P < .01]; and eGFR<60 vs.≥60 [OR = 1.22, P = .04] were independent risk factors for hypertension in women. Age and diabetes were independent risk factors for the participants with hypertension [OR = 1.04, P < .01] and [OR = 2.24, P < .01]. High quartile SUA group has increased the risk for hypertension in postmenopausal women [OR = 1.34, P = .048]. We found that postmenopausal women have high SUA compared to premenopausal women. The high SUA quartiles uric acid may be an independent risk for hypertension in postmenopausal women.
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Hipertensión , Posmenopausia/fisiología , Ácido Úrico/sangre , Índice de Masa Corporal , China/epidemiología , Estudios Transversales , Etnicidad , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hipertensión/metabolismo , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
Oxidative stress injury is one of the main mechanisms of ischemia-reperfusion (I/R) injury. The extracellular signal-regulated kinase (ERK1/2) pathway plays an important role in cardioprotective during acute myocardial infarction. In this study, we used constitutively active MEK1 gene (CaMEK) transfection strategy to investigate whether CaMEK provides a protective effect against apoptosis and autophagy induced by Hydrogen peroxide (H2O2) in neonatal rat cardiac ventricular cardiomyocytes (NCMs) and the underlying mechanisms. As a result, CaMEK attenuated H2O2-induced apoptosis and cytotoxicity in NCMs, evidenced by decreased apoptotic cells and the ratio of Bax/Bcl-2, increased the mitochondrial membrane potential (Δψm) and cell vitality and reduced the level of lactate dehydrogenase (LDH). Further studies revealed that CaMEK attenuated H2O2-induced autophagy, evidenced by the decreased LC3-â ¡/LC3-â ratio and SQSTM1/p62 (p62) degradation. Furthermore, we demonstrated that CaMEK phosphorylated the ERK1/2 pathway-related proteins, ERK1/2, p70S6K and GSK3ß, in NCMs with H2O2 stimulation. In contrast, these effects could be reversed by co-treatment with the ERK1/2 inhibitor, PD98059. These results suggest that CaMEK plays an important role in protecting cardiomyocytes against H2O2-induced injury and autophagy in NCMs via ERK1/2 pathway. Therefore, transfection of CaMEK may provide a hopeful therapeutic strategy for I/R.
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MAP Quinasa Quinasa 1/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cardiotónicos/metabolismo , Células Cultivadas , Femenino , Peróxido de Hidrógeno/toxicidad , MAP Quinasa Quinasa 1/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , TransfecciónRESUMEN
Ischemic preconditioning (IPC) is an endogenous protection strategy against myocardial ischemia-reperfusion (I/R) injury. Macrophage migration inhibitory factor (MIF) released from the myocardium subjected to brief periods of ischemia confers cardioprotection. We hypothesized that MIF plays an essential role in IPC-induced cardioprotection. I/R was induced either ex vivo or in vivo in male wild-type (WT) and MIF knockout (MIFKO) mice with or without proceeding IPC (three cycles of 5-min ischemia and 5-min reperfusion). Indices of myocardial injury, regional inflammation and cardiac function were determined to evaluate the extent of I/R injury. Activations of the reperfusion injury salvage kinase (RISK) pathway, AMP-activated protein kinase (AMPK) and their downstream components were investigated to explore the underlying mechanisms. IPC conferred prominent protection in WT hearts evidenced by reduced infarct size (by 33-35%), myocyte apoptosis and enzymatic markers of tissue injury, ROS production, inflammatory cell infiltration and MCP1/CCR2 expression (all P<0.05). IPC also ameliorated cardiac dysfunction both ex vivo and in vivo These protective effects were abolished in MIFKO hearts. Notably, IPC mediated further activations of RISK pathway, AMPK and the membrane translocation of GLUT4 in WT hearts. Deletion of MIF blunted these changes in response to IPC, which is the likely basis for the absence of protective effects of IPC against I/R injury. In conclusion, MIF plays a critical role in IPC-mediated cardioprotection under ischemic stress by activating RISK signaling pathway and AMPK. These results provide an insight for developing a novel therapeutic strategy that target MIF to protect ischemic hearts.
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Oxidorreductasas Intramoleculares/metabolismo , Precondicionamiento Isquémico Miocárdico/métodos , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Oxidorreductasas Intramoleculares/deficiencia , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/deficiencia , Factores Inhibidores de la Migración de Macrófagos/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Receptores CCR2/metabolismo , Transducción de Señal , Remodelación VentricularRESUMEN
BACKGROUND: The study was designed to investigate lipid profile and SYNTAX score in patients with non-ST segment elevation myocardial infarction (NSTEMI). METHODS: 311 patients with NSTEMI were enrolled. The demographic, clinical data, blood samples and SYNTAX score were documented. The Pearson linear correlation was used to detect confounding factors linearly correlated with SYNTAX score. The significantly correlated confounding factors were put into the multiple linear regressions. RESULTS: The Pearson linear correlation showed that high-density lipoprotein- cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) were significantly correlated with Syntax Score (r = - 0.119, P = 0.044 and r = - 0.182, P = 0.002, respectively). The multiple linear regressions for Syntax Score were built using HDL-C and ApoA1, respectively. After the adjustment of other significantly correlated confounding factors such as white blood cell count (WBC), myohemoglobin (MB), glutamic-oxalacetic transaminase (AST) and creatinine, the ApoA1 still showed significant association with Syntax Score (ß = - 0.151, P = 0.028). The area under curve was (AUC) 0.624 and the optimal cutoff value is 1.07 g/L when using ApoA1 to predict moderate and severe coronary artery lesions. The patients with ApoA1 ≥ 1.07 g/L and < 1.07 g/L have the Syntax Scores of 12.21 ± 11.58 and 16.33 ± 11.53, respectively (P = 0.001). CONCLUSIONS: The ApoA1 is the only lipid factor significantly associated with complexity of coronary artery lesion in patients with NSTEMI, the patients with ApoA1 < 1.07 g/L may have more complex coronary artery lesions.
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Apolipoproteína A-I/sangre , Infarto del Miocardio sin Elevación del ST/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , HDL-Colesterol/sangre , Creatinina/sangre , Estudios Transversales , Femenino , Humanos , Recuento de Leucocitos , Modelos Lineales , Masculino , Persona de Mediana Edad , Mioglobina/sangre , Infarto del Miocardio sin Elevación del ST/sangre , Infarto del Miocardio sin Elevación del ST/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: This study was designed to investigate whether differential DNA methylationin of cholesterol absorption candidate genes can function as a biomarker for patients with coronary heart disease (CHD). METHODS: DNA methylation levels of the candidate genes FLOT1, FLOT2 and SOAT1 were measured in peripheral blood leukocytes (PBLs) from 99 patients diagnosed with CHD and 89 control subjects without CHD. A total of 110 CPG sites around promoter regions of them were examined. RESULTS: Compared with groups without CHD, patients with CHD had lower methylation levels of SOAT1 (P<0.001). When each candidate genes were divided into different target segments, patients with CHD also had lower methylation levels of SOAT1 than patients without (P = 0.005). After adjustment of other confounders, methylation levels of SOAT1 were still associated with CHD (P = 0.001, OR = 0.290, 95% CI: 0.150-0.561). CONCLUSIONS: SOAT1 methylation may be associated with development of CHD. Patients with lower methylation levels in SOAT1 may have increased risks for CHD. Further studies on the specific mechanisms of this relationship are necessary.
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Enfermedad Coronaria/genética , Metilación de ADN/genética , Esterol O-Aciltransferasa/genética , Anciano , Islas de CpG/genética , Femenino , Genotipo , Humanos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Factores de RiesgoRESUMEN
BACKGROUND: Limited information is available when it comes to the impact of genetic on Calcific Aortic Stenosis (CAS). Apolipoprotein B (apoB) is a key component in lipid metabolism and plays an important role in the dynamic equilibrium of cholesterol. We performed a case-control study to explore the association of apoB genetic polymorphisms with CAS in Chinese subjects, in Xinjiang, China. METHODS: We designed a case-control study including 314 CAS patients and 652 age- and sex-matched control subjects. Using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method, we genotyped two SNPs (rs6725189 and rs693) of apoB gene in all subjects. RESULTS: We found that the rs693 T allele was associated with a significantly elevated CAS risk [TT/CT vs. CC: adjusted odds ratio (AOR) = 1.58, 95% confidence interval (CI) = 1.82-2.10, P = 0.002] and the rs6725189 T allele was also associated with a significantly elevated CAS risk (GT vs. GG: AOR = 1.82, 95% CI = 1.14-2.92, P = 0.013). Furthermore, we also found that the TC levels were significantly higher in rs693 TT/CT genotypes than that in CC genotypes (P < 0.05). CONCLUSIONS: Both rs693 and rs6725189 of the apoB gene are associated with CAS in Chinese subjects, in Xinjiang, China.
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Estenosis de la Válvula Aórtica/genética , Válvula Aórtica/patología , Apolipoproteína B-100/genética , Calcinosis/genética , Polimorfismo de Nucleótido Simple , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Lípidos/sangre , Lípidos/genética , Masculino , Persona de Mediana EdadRESUMEN
Nuclear factor κappa B (NF-κB) is an important transcription factor in the development and progression of coronary artery disease (CAD). Recent evidence suggests that -94 ATTG ins/del mutant in the promoter of NFKB1 gene is an essential functional mutant. The present study demonstrated the frequencies of the del/del (DD) genotype and del (D) allele were significantly higher in CAD patients than in controls. CAD patients carrying mutant DD genotype had worse stenosis of diseased coronary arteries compared to those carrying ins/ins (II) or ins/del (ID) genotype. Plasma levels of endothelial nitric oxide synthase (eNOS) were lower, while inflammatory cytokine incnterlukin-6 (IL-6) was higher in CAD patients with DD genotype than those with II or ID genotype (both P<0.05). In vitro study showed that mutant human umbilical vein endothelial cells (DD genotype HUVECs) were more susceptible to H2O2-induced apoptosis, which was accompanied with a decreased Bcl-2 expression. Further, mutant HUVECs had lower eNOS but higher IL-6 mRNA levels and decreased phosphorylation of eNOS under H2O2-stimulation (both P<0.05). Compared to wild type cells (II genotype), significantly downregulated protein expression of total NF-κB p50 subunit were observed in mutant HUVECs with or without oxidative stress, and a lower expression of unclear p50 was associated with a decreased p50 nuclear translocation in mutant HUVECs versus wild type cells under H2O2-stimulation (both P<0.05). In conclusion, mutant DD genotype of NFKB1 gene is associated with the risk and severity of CAD. Dwonregulation of NF-κB p50 subunit leads to exacerbated endothelial dysfunction and apoptosis and enhanced inflammatory response that is the potential underlying mechanism.
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Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Genotipo , Mutación , Subunidad p50 de NF-kappa B/genética , Anciano , Alelos , Apoptosis/efectos de los fármacos , Biomarcadores , Enfermedad de la Arteria Coronaria/metabolismo , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Femenino , Expresión Génica , Estudios de Asociación Genética , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/metabolismo , Subunidad p52 de NF-kappa B/genética , Subunidad p52 de NF-kappa B/metabolismo , Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: In animal models, secreted frizzled related protein 1 (Sfrp1) inhibition of the Wnt signaling pathway is beneficial because Sfrp1 reduces myocardial apoptosis and prevents heart failure. The mechanisms mediating the cellular survival effect of Sfrp1 has not been completely elucidated. The present study was designed to investigate the possible protective actions of Sfrp1 on cardiac muscle cells using an in vitro model of ischemia/reperfusion, and to evaluate the possible involvement of the Wnt signaling pathway. METHODS: We used a recombinant AAV9 vector to deliver the Sfrp1 gene into H9C2 rat cardiomyoblasts and adopted an in vitro model of ischemia/reperfusion. Cell vitality was measured by CKK-8 and the trypan blue exclusion assay. Western blot was used to evaluate the expression of Dvl-1, ß-catenin, c-Myc, Bax, and Bcl-2. Flow cytometry analysis of cardiomyocyte apoptosis was performed. RESULTS: We confirmed that Sfrp1 significantly increased cell viability (assayed by trypan blue and CKK-8) and decreased apoptosis (assayed by flow cytometry analysis and the Bax/Bcl-2 ratio). These effects were partly attributable to the ability of Sfrp1 to down-regulate Wnt signaling pathway (assayed by Western blot to evaluate the expression of Dvl-1, ß-catenin, and c-Myc). Indeed, reactivation of the Wnt signaling pathway activity with the specific activator, Licl, reduced Sfrp1-induced cardioprotection during hypoxia and reoxygenation. CONCLUSIONS: The present study demonstrated that Sfrp1 directly protected H9C2 cells from hypoxia and reoxygenation-induced reperfusion injury and apoptosis through inhibition of the Wnt signaling pathway, and added new mechanistic insight regarding the cardioprotective role of Sfrp1 on ischemic damage.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Miocardio/metabolismo , Vía de Señalización Wnt , Animales , Apoptosis , Hipoxia de la Célula/fisiología , Línea Celular , Supervivencia Celular , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/citología , Miocardio/patología , Ratas , Proteína X Asociada a bcl-2/metabolismo , beta Catenina/metabolismoRESUMEN
OBJECTIVES: The aim of this study was to evaluate the impact of mean platelet volume (MPV) on the intracoronary thrombus burden and short-term mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Platelets play a crucial role in the pathophysiology of coronary artery disease. MPV has been reported to be an indicator of platelet reactivity. METHODS: A total of 649 consecutive STEMI patients who underwent primary PCI between January 2008 and December 2013 were enrolled and divided into two groups based on the thrombus burden: the large thrombus burden (LTB) group and the small thrombus burden (STB) group. The primary endpoint was all-cause mortality at 30 days. RESULT: The LTB group had significantly higher admission MPV compared with the STB group (10.77 ± 1.22 vs. 9.95 ± 1.03, P < 0.001). The cumulative 30-day all-cause mortality rate was significantly higher in the groups with high MPV and LTB (9.8% vs. 2.5%, P < 0.001, 8.6% vs. 4.1%, P = 0.036, respectively). In a receiver operating characteristics analysis, MPV ≥ 10.2 predicted LTB with 73.5% sensitivity and 68.9% specificity. Multivariate logistic regression analysis demonstrated MPV was an independent predictor of large intracoronary thrombus burden (OR 1.794, 95% CI 1.533 to 2.100, P < 0.001) and 30-day all-cause mortality (HR 1.408, 95% CI 1.040 to 1.906, P = 0.027). CONCLUSIONS: Increased MPV at admission is an independent predictor of large intracoronary thrombus burden and short-term mortality. It may be a useful biomarker for risk stratification in patients with STEMI undergoing primary PCI. © 2015 Wiley Periodicals, Inc.
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Angiografía Coronaria , Trombosis Coronaria/terapia , Volúmen Plaquetario Medio , Infarto del Miocardio/sangre , Infarto del Miocardio/terapia , Intervención Coronaria Percutánea/mortalidad , Anciano , Área Bajo la Curva , Distribución de Chi-Cuadrado , Trombosis Coronaria/sangre , Trombosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/mortalidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/mortalidad , Oportunidad Relativa , Selección de Paciente , Intervención Coronaria Percutánea/efectos adversos , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Adeno-associated virus (AAV) has become one of the most promising gene transfer tools for gene therapy. This work aims to evaluate tropism, gene transfer efficiency and safety of AAV9 vectors produced with recombinant baculovirus (rBac)-based system. AAV9-CMV-GFP and AAV9-CBA-GFP were produced using a rBac system, 1 × 10(11) particles of each vectors were administered intravenously (i.v.) into mice and animals were killed at 1, 2, 3, 4, 5 and 8 weeks after administration. The GFP expression in different organs was analyzed by fluorescence imaging and Western blot. Viral genomic quantities were measured using qPCR. In vitro transduction efficiency of AAV9 vectors in primary cardiomyocytes and hepatocytes was determined by flow cytometry. Toxicity of AAV9 vectors was evaluated by determining certain cardiac and liver injury biomarkers and renal function test in vivo and TUNEL analysis in vitro. The data showed that AAV9 viral particles packaged by the rBac system were fully functional in vivo and in vitro. The CMV promoter predominantly induced higher cardiac GFP transgene expression and DNA copy numbers while the CBA promoter resulted in robust GFP expression and high vector DNA copy numbers in mouse liver, both in a time-dependent increased manner. Such distinct preferential effects were also observed in the heart and liver as early as 3 and 5 days after co-infection. Both the AAV9-CMV and AAV9-CBA viral packages did not induce heart, liver and renal damage and cell apoptosis. These results indicated that AAV9-CMV can efficiently and safely direct cardiac gene transfer, whereas AAV9-CBA is preferential for liver gene delivery.
Asunto(s)
Dependovirus/genética , Hepatocitos/metabolismo , Miocitos Cardíacos/metabolismo , Regiones Promotoras Genéticas/genética , Transducción Genética/métodos , Transgenes/genética , Actinas/genética , Animales , Apoptosis/genética , Pollos/genética , Citomegalovirus/genética , Dependovirus/fisiología , Vectores Genéticos/genética , Hepatocitos/citología , Hepatocitos/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/citología , Miocitos Cardíacos/virología , Seguridad , Tropismo ViralRESUMEN
BACKGROUND: Plasminogen activator inhibitor -2 (PAI-2) is an important molecular that plays a crucial role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury, such as atherosclerosis, coronary artery disease (CAD). METHODS: The aim of the current study was to explore the association between the variants in PAI-2 gene and CAD and its prognoses. The three variants (rs8093048, rs9946657, rs9320032) of the PAI-2 gene were detected in 407 patients with CAD and 518 control subjects. All patients with CAD underwent one-year follow-up for major adverse cardiac events (MACE). RESULTS: The frequencies of the TT genotype and T allele of rs8093048 was significantly higher in CAD patients than that in control subjects (7.6% vs.3.5%, P = 0.003, 28.1 % vs.21.7%, P < 0.001, respectively). Multifactor logistic regression analysis showed that the TT genotype of rs8093048 was a risk factor for CAD (OR = 1.455, 95 % CI: 1.069-1.980, P = 0.017). In addition, the follow-up data showed that CAD patients with rs8093048 TT genotype had significantly higher rate of refractory angina and MACE than those with CC or CT genotype (P = 0.032, P = 0.009, respectively). Cox regression analysis showed that rs8093048 TT genotype was the risk factor for the MACE (Hazard ratio = 5.672, 95% CI = 1.992-16.152, P = 0.001). CONCLUSION: We firstly found that the variant of PAI-2 gene was associated with CAD and recurrent coronary event risk in Chinese Han population, in Xinjiang.
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Enfermedad de la Arteria Coronaria/genética , Inhibidor 2 de Activador Plasminogénico/genética , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Enfermedad de la Arteria Coronaria/mortalidad , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
BACKGROUND: Lately, there is accumulating evidence that the Wnt/Frizzled pathway is reactivated after myocardial infarction, the inhibition of the pathway is beneficial since it reduce of myocardial apoptosis and prevents heart failure. FrzA/Sfrp-1, a secreted frizzled-related protein and antagonist for the wnt/frizzled pathway. We assessed the hypothesis that FrzA protects cardiomyocytes from H2O2-Induced Oxidative damage through the inhibition of Wnt/Frizzled pathway activity. METHODS: We used a recombinant AAV9 vector to deliver FrzA gene into neonatal rat ventricle myocytes and developed an oxidative stress model using H2O2. The cell vitality was measured by MTT colorimetric assay. Western blot and RT-PCR were used to evaluate the expressions of Dvl-1, ß-catenin, c-Myc, Bax and Bcl-2. Flow cytometry analysis of cardiomyocytes apoptosis. RESULTS: We confirmed that Wnt/frizzled pathway is involved in H2O2-induced apoptosis in cardiomyocytes. Compared with controls, H2O2 induced the upregulation of Dvl-1, ß-catenin, and c-Myc. FrzA suppressed the expression of Dvl-1, ß-catenin, c-Myc and the activity of the Wnt/frizzled pathway. Furthermore, FrzA over-expression decreased the apoptotic rate, and the Bax/Bcl-2 ratio in cardiomyocytes treated with H2O2. CONCLUSIONS: FrzA, through the inhibition of Wnt/Frizzled pathway activity reduced H2O2-induced cardiomyocytes apoptosis and could be a potential therapeutic target for prevention of cardiac oxidative damage.
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Peróxido de Hidrógeno/farmacología , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Miocitos Cardíacos/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Animales Recién Nacidos , Apoptosis/genética , Dependovirus/genética , Proteínas Dishevelled , Regulación de la Expresión Génica , Vectores Genéticos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Estrés Oxidativo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas , Transducción de Señal , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: CYP17A1 gene encodes P450c17 proteins, which is a key enzyme that catalyzes the formation of sex hormones. Many clinical studies showed that sex hormones levels play an important role in the pathogenesis of coronary artery disease (CAD). However, the relationship between CYP17A1 genetic polymorphisms and CAD remains unclear. The aim of this study was to investigate the association of CYP17A1 genetic polymorphisms with CAD in a Han population of China. METHODS: A total of 997 people include 490 patients and 507 controls were selected for the present study. Five single-nucleotide polymorphisms (SNPs) (rs4919686, rs1004467, rs4919687, rs10786712, and rs2486758) were genotyped by using the real-time PCR (TaqMan) method. RESULTS: For men, the rs10786712 was found to be associated with CAD in a recessive model (P=0.016), after adjustment of the major confounding factors, the significant difference was retained (OR=1.644, 95% confidence interval [CI]: 1.087-2.488, P=0.019). For women, the rs1004467 was also found to be associated with CAD in a dominant model (P=0.038), the difference remained statistically significant after multivariate adjustment (OR=1.623, 95% CI: 1.023-2.576, P=0.040). The distribution of rs4919687 genotypes showed a significant difference between CAD and control participants in a recessive model (P=0.019), the significant difference was retained after adjustment for covariates (OR=0.417, 95% CI: 0.188-0.926, P=0.032). CONCLUSION: Rs1004467, rs4919687, rs10786712 of CYP17A1 gene are associated with CAD in Han population of China. The TT genotype of rs10786712 could be a protective genetic marker of CAD in men. The CC genotype of rs1004467 and the AA genotype of rs4919687 could be risk genetic markers of CAD in women. However, large sample size study including other SNPs of CYP17A1 should be performed in future studies.
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Enfermedad de la Arteria Coronaria/genética , Polimorfismo de Nucleótido Simple/genética , Esteroide 17-alfa-Hidroxilasa/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Femenino , Genes Dominantes/genética , Genes Recesivos/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores SexualesRESUMEN
BACKGROUND: Hypercholesterolemia is a major risk factor for coronary artery disease (CAD). As Numb is an important regulating factor for intestinal cholesterol absorption and plasma cholesterol level, the aim of the present study is to assess the association between human Numb gene polymorphism and CAD among Han and Uighur Chinese. METHODS: We have conducted two independent case-control studies in Han Chinese (384 CAD patients and 433 controls) and Uighur Chinese (506 CAD patients and 351 controls) subjects. All subjects were genotyped for four kinds of SNPs (rs12435797, rs2108552, rs1019075 and rs17781919) and SNP is used as a genetic marker for human Numb gene. Genotyping was undertaken using TaqMan SNP genotyping assay, and the subjects' ethnicity and gender were considered in the analysis. RESULTS: We found that rs2108552 was associated with CAD in the dominant model (CC vs CG + GG) for the total Han Chinese population (n = 200) and Han Chinese males (n = 115) (P = 0.004 and P = 0.001, respectively). The difference remained statistically significant after multivariate adjustment (total: OR = 1.687, P = 0.004; male: OR = 1.498, P = 0.006). Further, for the total (n = 817) and male (n = 490) Han Chinese, the frequency of the haplotype (T-C-T-C) was significantly higher in the CAD patients than in the controls (P = 0.004 and P = 0.002), and the frequency of the haplotype (G-G-T-C) was significantly lower in the CAD patients than in the control subjects (P = 0.013, P = 0.007). In addition, for the total (n = 857) and male (n = 582) Uighur Chinese, we observed that rs12435797 was associated with CAD in an additive and recessive model (P = 0.021 and P = 0.009; P = 0.048 and P = 0.034). However, the difference did not remain statistically significant after multivariate adjustment. The overall distribution of rs2108552, rs1019075 and rs17781919 genotypes, alleles and the frequency of the haplotype established by four SNPs showed no significant difference between CAD patients and control subjects in the total, male and female Uighur Chinese. CONCLUSIONS: The results of this study indicate that CC genotype of rs2108552 and T-C-T-C haplotypes in Numb gene is a possible risk genetic marker and G allele and G-G-T-C haplotypes is a possible protective genetic marker for CAD in male Han Chinese.
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Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Hipercolesterolemia/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Alelos , Transporte Biológico , Estudios de Casos y Controles , China , Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/etnología , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/metabolismo , Etnicidad , Femenino , Expresión Génica , Frecuencia de los Genes , Haplotipos , Humanos , Hipercolesterolemia/complicaciones , Hipercolesterolemia/etnología , Hipercolesterolemia/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Modelos Genéticos , Proteínas del Tejido Nervioso/metabolismo , Factores de RiesgoRESUMEN
BACKGROUND: The optimal cutoff of the waist-to-hip ratio (WHR) among Han adults in Xinjiang, which is located in the center of Asia, is unknown. We aimed to examine the relationship between different WHRs and cardiovascular risk factors among Han adults in Xinjiang, and determine the optimal cutoff of the WHR. METHODS: The Cardiovascular Risk Survey was conducted from October 2007 to March 2010. A total of 14618 representative participants were selected using a four-stage stratified sampling method. A total of 5757 Han participants were included in the study. The present statistical analysis was restricted to the 5595 Han subjects who had complete anthropometric data. The sensitivity, specificity, and distance on the receiver operating characteristic (ROC) curve in each WHR level were calculated. The shortest distance in the ROC curves was used to determine the optimal cutoff of the WHR for detecting cardiovascular risk factors. RESULTS: In women, the WHR was positively associated with systolic blood pressure, diastolic blood pressure, and serum concentrations of serum total cholesterol. The prevalence of hypertension and hypertriglyceridemia increased as the WHR increased. The same results were not observed among men. The optimal WHR cutoffs for predicting hypertension, diabetes, dyslipidemia and ≥ two of these risk factors for Han adults in Xinjiang were 0.92, 0.92, 0.91, 0.92 in men and 0.88, 0.89, 0.88, 0.89 in women, respectively. CONCLUSIONS: Higher cutoffs for the WHR are required in the identification of Han adults aged ≥ 35 years with a high risk of cardiovascular diseases in Xinjiang.
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Pueblo Asiatico , Enfermedades Cardiovasculares/etnología , Obesidad/diagnóstico , Obesidad/etnología , Relación Cintura-Estatura , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Biomarcadores/sangre , Presión Sanguínea , China/epidemiología , Femenino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/etnología , Hipertensión/diagnóstico , Hipertensión/etnología , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/etnología , Lípidos/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Factores de Riesgo , Factores SexualesRESUMEN
BACKGROUND: The cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) gene is expressed in the vascular endothelium, which metabolizes arachidonic acid into 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs). 20-HETE mediates cardiovascular homeostasis and growth response in vascular smooth muscle cells (VSMCs) as well as the anti-platelet effect. EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. This study assessed the association between human CYP1A1 gene polymorphisms and coronary artery disease (CAD) in the Uygur and Han in China. METHODS: Two independent case-control studies that recruited Han (389 patients with CAD and 411 controls) and Uygur participants (293 patients with CAD and 408 controls) analyzed the relationship between CYP1A1 single nucleotide polymorphisms (SNPs: rs4886605, rs12441817, rs4646422 and rs1048943) and CAD. All patients with CAD and controls were genotyped for the four SNPs of CYP1A1 using TaqMan SNP genotyping assays. RESULTS: In the Uygur group, the distribution of the dominant model(CC vs CT + TT) of rs4886605 for the total sample and the males was significantly different between CAD patients and control participants (P = 0.001 and P = 0.012, respectively), The difference remained significant after a multivariate adjustment (P = 0.018, P = 0.015, respectively). The rs12441817 was also associated with CAD in a dominant model for all participants (P = 0.003) and men (P = 0.012), and the difference remained significant after a multivariate adjustment (P = 0.016, P = 0.002, respectively). However, we did not observe differences in the Uygur females and Han group with regard to the allele frequency or genotypic distribution of rs4886605 and rs12441817 between patients with CAD and control participants. Patients with CAD did not significantly differ from the control participants with regard to the distributions of rs4646422 and rs1048943 genotypes, the dominant model, the recessive model, or allele frequency in the Han and Uygur groups. CONCLUSION: Both rs4886605 and rs12441817 SNPs of the CYP1A1 gene are associated with CAD in the Uygur population of China.