RESUMEN
Yohimbine (YHB) has been reported to possess anti-inflammatory, anticancer, and cardiac function-enhancing properties. Additionally, it has been reported to inhibit the proliferation, migration, and neointimal formation of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) stimulation by suppressing the phospholipase C-gamma 1 pathway. However, the transcriptional regulatory mechanism of YHB controlling the behavior of VSMCs is not fully understood. In this study, YHB downregulated the expression of cell cycle regulatory proteins, such as proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin-dependent kinase 4 (CDK4), and cyclin E, by modulating the transcription factor FOXO3a in VSMCs induced by PDGF. Furthermore, YHB decreased p-38 and mTOR phosphorylation in a dose-dependent manner. Notably, YHB significantly reduced the phosphorylation at Y397 and Y925 sites of focal adhesion kinase (FAK), and this effect was greater at the Y925 site than Y397. In addition, the expression of paxillin, a FAK-associated protein known to bind to the Y925 site of FAK, was significantly reduced by YHB treatment in a dose-dependent manner. A pronounced reduction in the migration and proliferation of VSMCs was observed following co-treatment of YHB with mTOR or p38 inhibitors. In conclusion, this study shows that YHB inhibits the PDGF-induced proliferation and migration of VSMCs by regulating the transcription factor FOXO3a and the mTOR/p38/FAK signaling pathway. Therefore, YHB may be a potential therapeutic candidate for preventing and treating cardiovascular diseases such as atherosclerosis and vascular restenosis.
Asunto(s)
Movimiento Celular , Proliferación Celular , Proteína Forkhead Box O3 , Músculo Liso Vascular , Miocitos del Músculo Liso , Factor de Crecimiento Derivado de Plaquetas , Yohimbina , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Proteína Forkhead Box O3/metabolismo , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Animales , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Fosforilación/efectos de los fármacos , Yohimbina/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Células Cultivadas , Paxillin/metabolismo , Ratas Sprague-Dawley , MasculinoRESUMEN
The long-term prognostic significance of maximal infarct transmurality evaluated by contrast-enhanced cardiac magnetic resonance (CE-CMR) in ST-segment elevation myocardial infarction (STEMI) patients has yet to be determined. This study aimed to see if maximal infarct transmurality has any additional long-term prognostic value over other CE-CMR predictors in STEMI patients, such as microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). The study included 112 consecutive patients who underwent CE-CMR after STEMI to assess established parameters of myocardial injury as well as the maximal infarct transmurality. The primary clinical endpoint was the occurrence of major adverse cardiac events (MACE), which included all-cause death, non-fatal reinfarction, and new heart failure hospitalization. The MACE occurred in 10 patients over a median follow-up of 7.9 years (IQR, 5.8 to 9.2 years) (2 deaths, 3 nonfatal MI, and 5 heart failure hospitalization). Patients with MACE had significantly higher rates of transmural extent of infarction, infarct size >5.4 percent, MVO, and IMH compared to patients without MACE. In stepwise multivariable Cox regression analysis, the transmural extent of infarction defined as 75 percent or more of infarct transmurality was an independent predictor of the MACE after correction for MVO and IMH (hazard ratio 8.7, 95% confidence intervals [CIs] 1.1-71; p=0.043). In revascularized STEMI patients, post-infarction CE-CMR-based maximal infarct transmurality is an independent long-term prognosticator. Adding maximal infarct transmurality to CE-CMR parameters like MVO and IMH could thus identify patients at high risk of long-term adverse outcomes in STEMI.
RESUMEN
Abnormal communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) promotes vascular diseases, including atherogenesis. ETS variant transcription factor 2 (ETV2) plays a substantial role in pathological angiogenesis and the reprogramming of ECs; however, the role of ETV2 in the communication between ECs and VSMCs has not been revealed. To investigate the interactive role of ETV2 in the EC to VSMC phenotype, we first showed that treatment with a conditioned medium from ETV2-overexpressed ECs (Ad-ETV2 CM) significantly increased VSMC migration. The cytokine array showed altered levels of several cytokines in Ad-ETV2 CM compared with those in normal CM. We found that C-X-C motif chemokine 5 (CXCL5) promoted VSMC migration using the Boyden chamber and wound healing assays. In addition, an inhibitor of C-X-C motif chemokine receptor 2 (CXCR2) (the receptor for CXCL5) significantly inhibited this process. Gelatin zymography showed that the activities of matrix metalloproteinase (MMP)-2 and MMP-9 increased in the media of VSMCs treated with Ad-ETV2 CM. Western blotting revealed a positive correlation between Akt/p38/c-Jun phosphorylation and CXCL5 concentration. The inhibition of Akt and p38-c-Jun effectively blocked CXCL5-induced VSMC migration. In conclusion, CXCL5 from ECs induced by ETV2 promotes VSMC migration via MMP upregulation and the activation of Akt and p38/c-Jun.
Asunto(s)
Músculo Liso Vascular , Proteínas Proto-Oncogénicas c-akt , Células Cultivadas , Células Endoteliales , Movimiento Celular , Citocinas/farmacología , Miocitos del Músculo LisoRESUMEN
BACKGROUND: Epidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined. RESULTS: VSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significantly increased in ambient PM-treated VSMCs, with MMP9 levels being significantly higher in WPM-treated VSMCs than in those treated with SPM. As expected, migration was significantly increased in all tested PAHs (anthracene, ANT; benz(a)anthracene, BaA) and their oxygenated derivatives (9,10-Anthraquinone, AQ; 7,12-benz(a)anthraquinone, BAQ, respectively). The phosphorylated levels of focal adhesion kinase (FAK) and formation of the focal adhesion complex were significantly increased in ambient PM or PAH-treated VSMCs, and these effects were blocked by administration of NAC or α-NF, an inhibitor of AhR, the receptor that allows PAH uptake. Subsequently, the levels of phosphorylated Src and NRF, the downstream targets of FAK, were altered with a pattern similar to that of p-FAK. CONCLUSIONS: PAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.
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Contaminantes Atmosféricos , Aterosclerosis , Hidrocarburos Policíclicos Aromáticos , Actinas , Contaminantes Atmosféricos/análisis , Movimiento Celular , Humanos , Metaloproteinasas de la Matriz , Músculo Liso Vascular/química , Estrés Oxidativo , Material Particulado/análisis , Material Particulado/toxicidad , Hidrocarburos Policíclicos Aromáticos/análisis , Hidrocarburos Policíclicos Aromáticos/toxicidad , Regulación hacia ArribaRESUMEN
The abnormal change of vascular smooth muscle cell (VSMC) behavior is an important cellular event leading to neointimal hyperplasia in atherosclerosis and restenosis. Plantamajoside (PMS), a phenylethanoid glycoside compound of the Plantago asiatica, has been reported to have anti-inflammatory, antioxidative, and anticancer activities. In this study, the protective effects of PMS against intimal hyperplasia and the mechanisms underlying the regulation of VSMC behavior were investigated. MTT and BrdU assays were performed to evaluate the cytotoxicity and cell proliferative activity of PMS, respectively. Rat aortic VSMC migrations after treatment with the determined concentration of PMS (50 and 150 µM) were evaluated using wound healing and Boyden chamber assays. The inhibitory effects of PMS on intimal hyperplasia were evaluated in balloon-injured (BI) rat carotid artery. PMS suppressed the proliferation in platelet-derived growth factor-BB-induced VSMC, as confirmed from the decrease in cyclin-dependent kinase (CDK)-2, CDK-4, cyclin D1, and proliferating cell nuclear antigen levels. PMS also inhibited VSMC migration, consistent with the downregulated expression and zymolytic activities of matrix metalloproteinase (MMP)2, MMP9, and MMP13. PMS specifically regulated MMP expression through p38 mitogen-activated protein kinase and focal adhesion kinase pathways. Tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2 levels were upregulated via Smad1. TIMPs inhibited the conversion of pro-MMPs to active MMPs. PMS significantly inhibited neointimal formation in BI rat carotid arteries. In conclusion, PMS inhibits VSMC proliferation and migration by upregulating TIMP1 and TIMP2 expression. Therefore, PMS could be a potential therapeutic agent for vascular atherosclerosis and restenosis treatment.
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Aterosclerosis , Neointima , Animales , Aterosclerosis/metabolismo , Catecoles , Movimiento Celular , Proliferación Celular , Células Cultivadas , Glucósidos , Hiperplasia/tratamiento farmacológico , Hiperplasia/metabolismo , Hiperplasia/patología , Músculo Liso Vascular , Miocitos del Músculo Liso , Neointima/tratamiento farmacológico , Neointima/metabolismo , Neointima/patología , Ratas , Ratas Sprague-Dawley , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Inhibidores Tisulares de Metaloproteinasas/farmacología , Inhibidores Tisulares de Metaloproteinasas/uso terapéutico , Regulación hacia ArribaRESUMEN
Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/ß-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/ß-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Isquemia Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Animales Recién Nacidos , Regulación de la Expresión Génica , Hidroxilación , Hipoxia/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Cultivo Primario de Células , Ratas , Vía de Señalización WntRESUMEN
Autodisplay of a multimeric protein complex on a cell surface is limited by intrinsic factors such as the types and orientations of anchor modules. Moreover, improper folding of proteins to be displayed often hinders functional cell surface display. While overcoming these drawbacks, we ultimately extended the applicability of the autodisplay platform to the display of a protein complex. We designed and constructed a cell surface attachment (CSA) system that uses a noncovalent protein-protein interaction. We employed the high-affinity interaction mediated by an orthogonal cohesin-dockerin (Coh-Doc) pair from Archaeoglobus fulgidus to build the CSA system. Then, we validated the orthogonal Coh-Doc binding by attaching a monomeric red fluorescent protein to the cell surface. In addition, we evaluated the functional anchoring of proteins fused with the Doc module to the autodisplayed Coh module on the surface of Escherichia coli. The designed CSA system was applied to create a functional attachment of dimeric α-neoagarobiose hydrolase to the surface of E. coli cells.
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Proteínas Arqueales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Técnicas de Visualización de Superficie Celular/métodos , Proteínas Cromosómicas no Histona/metabolismo , Secuencia de Aminoácidos , Proteínas Arqueales/química , Proteínas Arqueales/genética , Archaeoglobus fulgidus , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Disacaridasas/química , Disacaridasas/genética , Disacaridasas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Luminiscentes/química , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Unión Proteica , Pliegue de Proteína , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteína Fluorescente Roja , CohesinasRESUMEN
BACKGROUND: Epidemiologic studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with an increased risk of developing cardiovascular diseases, including arrhythmia. However, the cellular and molecular mechanisms by which PM exposure causes arrhythmia and the component that is mainly responsible for this adverse effect remains to be established. In this study, the arrhythmogenicity of mobilized organic matter from two different types of PM collected during summer (SPM) and winter (WPM) seasons in the Seoul metropolitan area was evaluated. In addition, differential effects between polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (oxy-PAHs) on the induction of electrophysiological instability were examined. RESULTS: We extracted the bioavailable organic contents of ambient PM, measuring 10 µm or less in diameter, collected from the Seoul metropolitan area using a high-volume air sampler. Significant alterations in all factors tested for association with electrophysiological instability, such as intracellular Ca2+ levels, reactive oxygen species (ROS) generation, and mRNA levels of the Ca2+-regulating proteins, sarcoplasmic reticulum Ca2+ATPase (SERCA2a), Ca2+/calmodulin-dependent protein kinase II (CaMK II), and ryanodine receptor 2 (RyR2) were observed in cardiomyocytes treated with PM. Moreover, the alterations were higher in WPM-treated cardiomyocytes than in SPM-treated cardiomyocytes. Three-fold more oxy-PAH concentrations were observed in WPM than SPM. As expected, electrophysiological instability was induced higher in oxy-PAHs (9,10-anthraquinone, AQ or 7,12-benz(a) anthraquinone, BAQ)-treated cardiomyocytes than in PAHs (anthracene, ANT or benz(a) anthracene, BaA)-treated cardiomyocytes; oxy-PAHs infusion of cells mediated by aryl hydrocarbon receptor (AhR) was faster than PAHs infusion. In addition, ROS formation and expression of calcium-related genes were markedly more altered in cells treated with oxy-PAHs compared to those treated with PAHs. CONCLUSIONS: The concentrations of oxy-PAHs in PM were found to be higher in winter than in summer, which might lead to greater electrophysiological instability through the ROS generation and disruption of calcium regulation.
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Potenciales de Acción/efectos de los fármacos , Contaminantes Atmosféricos/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Oxígeno/química , Material Particulado/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , Contaminantes Atmosféricos/química , Animales , Animales Recién Nacidos , Calcio/metabolismo , Células Cultivadas , Peroxidación de Lípido/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Tamaño de la Partícula , Material Particulado/química , Técnicas de Placa-Clamp , Hidrocarburos Policíclicos Aromáticos/química , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Estaciones del Año , SeúlRESUMEN
BACKGROUND: Cardiac hypertrophy is associated with functional changes in cardiomyocytes, which often results in heart failure. The low-density lipoprotein receptor-related protein 1 (LRP1) is a large multifunctional endocytic receptor involved in many physiological and pathological processes. However, its function in the development of cardiac hypertrophy remains largely unclear. METHODS: Adenoviral constructs were used for either overexpression or silencing of LRP1 in both in vitro and in vivo experiments. Cardiac function was measured using the Millar catheter. RESULTS: LRP1 expression was upregulated in both transverse aortic constriction (TAC)-induced hypertrophic myocardium and catecholamine (phenylephrine (PE) and norepinephrine (NE))- and angiotensin II (AngII)-induced hypertrophic cardiomyocytes. In addition, cell surface area, protein/DNA ratio, and the mRNA levels of hypertrophic markers were significantly increased in LRP1-overexpressing cardiomyocytes without catecholamine stimulation. Conversely, LRP1 inhibition by LRP1-specific siRNA or a specific ligand-binding antagonist (RAP) significantly rescued hypertrophic effects in PE, NE, or AngII-induced cardiomyocytes. LRP1 overexpression induced PKCα, then activated ERK, resulting in cardiac hypertrophy with the downregulation of SERCA2a and calcium accumulation, which was successfully restored in both LRP1-silenced cardiomyocytes and TAC-induced hearts. CONCLUSIONS: LRP1 regulates cardiac hypertrophy via the PKCα-ERK dependent signaling pathway resulting in the alteration of intracellular calcium levels, demonstrating that LRP1 might be a potential therapeutic target for cardiac hypertrophy.
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Cardiomegalia/metabolismo , Cardiomegalia/patología , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/biosíntesis , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Animales , Humanos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Previous studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs.
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Sistema de Señalización de MAP Quinasas , MicroARNs/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Factores de Transcripción/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Sitios de Unión , Proteínas de Unión al Calcio/genética , Familia de Proteínas EGF/genética , Elementos de Facilitación Genéticos/genética , Regulación de la Expresión Génica , Ratones , Regiones Promotoras Genéticas/genéticaRESUMEN
We hypothesized that the combination of a high neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) would be a stronger predictor of future cardiovascular events after percutaneous coronary intervention (PCI). Both NLR and MPV were measured in 364 consecutive patients undergoing PCI. The primary end point was the incidence of major adverse cardiovascular events (MACEs), including cardiac death, nonfatal myocardial infarction, and stent thrombosis. The median values of NLR and MPV were 2.8 and 8.2 fL, respectively. There were 26 MACEs during a median follow-up duration of 29.3 months. Kaplan-Meier analysis revealed that the higher NLR group had a significantly higher MACE rate than the lower NLR group and that the higher MPV group had a significantly higher MACE rate than the lower MPV group (log-rank: P = .0064 and P = .0004, respectively). The cumulative MACE-free survival can be further stratified by the combination of NLR and MPV. This value was especially useful in patients with acute coronary syndrome (ACS). By multivariate Cox proportional hazards model, the combination of high NLR and high MPV was independently associated with MACE ( P = .026). The combination of a high NLR and high MPV is an independent predictor of MACE after PCI, especially in patients with ACS.
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Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/cirugía , Angina Estable/sangre , Angina Estable/cirugía , Plaquetas , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/cirugía , Linfocitos , Neutrófilos , Intervención Coronaria Percutánea/efectos adversos , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/mortalidad , Anciano , Angina Estable/diagnóstico por imagen , Angina Estable/mortalidad , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/mortalidad , Trombosis Coronaria/sangre , Trombosis Coronaria/mortalidad , Femenino , Humanos , Recuento de Linfocitos , Masculino , Volúmen Plaquetario Medio , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/mortalidad , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/mortalidad , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , República de Corea/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Stents , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke) and CHA2 DS2 -VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) scores showed just moderate discrimination ability in predicting thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: To determine the association of antithrombin III (AT-III) deficiency and mean platelet volume (MPV) with the development of stroke or left atrial (LA) thrombus in patients with AF. METHODS: AT-III and MPV were analyzed in 352 patients with AF. The primary endpoint was a composite of ischemic stroke event and incidental LA thrombus. RESULTS: There were 50 events (14.2%) during a mean 35.4 months of follow-up. A significantly higher stroke or LA thrombus rate was observed in the low-AT-III group (<70%) than that in the high-AT-III group (≥70%). A significantly higher stroke or LA thrombus rate was observed in the high-MPV group (≥7.0 fL) than that in the low-MPV group (<7.0 fL). AF patients with an MPV ≥7.0 fL and AT-III deficiency had higher stroke or LA thrombus risk than those without an MPV ≥7.0 fL and AT-III deficiency. In the Cox proportional hazard analysis, high MPV was found to be an independent predictor of stroke or LA thrombus risk (hazard ratio: 6.408; 95% confidence interval: 2.874-14.286). Although AT-III deficiency was not an independent predictor of stroke or LA thrombus risk, a trend was observed. CONCLUSIONS: High MPV and AT-III deficiency were predictive markers for stroke or LA thrombus. Their predictive power for stroke was independent of antiplatelet treatment, anticoagulation therapy, and a high CHA2 DS2 -VASc score in patients with AF.
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Deficiencia de Antitrombina III/sangre , Antitrombina III/análisis , Fibrilación Atrial/sangre , Plaquetas/metabolismo , Isquemia Encefálica/sangre , Volúmen Plaquetario Medio , Accidente Cerebrovascular/sangre , Trombosis/sangre , Anciano , Anciano de 80 o más Años , Deficiencia de Antitrombina III/complicaciones , Deficiencia de Antitrombina III/diagnóstico , Deficiencia de Antitrombina III/mortalidad , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/mortalidad , Biomarcadores/sangre , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etiología , Isquemia Encefálica/mortalidad , Supervivencia sin Enfermedad , Ecocardiografía Transesofágica , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Trombosis/diagnóstico , Trombosis/etiología , Trombosis/mortalidadRESUMEN
Platelets are essential for progression of atherosclerotic lesions, plaque destabilization, and thrombosis. They secrete and express many substances that are crucial mediators of coagulation, inflammation, and atherosclerosis. Mean platelet volume (MPV) is a precise measure of platelet size, and is routinely reported during complete blood count analysis. Emerging evidence supports the use of MPV as a biomarker predicting the risk of ischemic stroke in patients with atrial fibrillation, and as a guide for prescription of anticoagulation and rhythm-control therapy. In addition, MPV may predict the clinical outcome of percutaneous coronary intervention (PCI) in patients with coronary artery disease and indicate whether additional adjunctive therapy is needed to improve clinical outcomes. This review focuses on the current evidence that MPV may be a biomarker of the risk and prognosis of common heart diseases, particularly atrial fibrillation and coronary artery disease treated via PCI.
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Plaquetas/metabolismo , Cardiopatías/sangre , Volúmen Plaquetario Medio , Activación Plaquetaria , Biomarcadores/sangre , Plaquetas/patología , Progresión de la Enfermedad , Cardiopatías/diagnóstico , Cardiopatías/mortalidad , Cardiopatías/terapia , Humanos , Valor Predictivo de las Pruebas , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The preprocedural neutrophil-lymphocyte ratio (NLR) is related to adverse outcomes in patients with coronary artery disease. We hypothesized that high NLR is a predictor of cardiac death after percutaneous coronary intervention (PCI). The objective of this investigation was to assess the associations of NLR, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) with the occurrence of cardiac death after PCI. MATERIALS AND METHODS: The NLR, hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary end point was cardiac death. RESULTS: The median NLR was 2.3 (interquartile range: 1.5-4.1). There were 21 cardiac death events during a mean follow-up duration of 25.8 months. With the NLR cutoff level set to 3.3 using the receiver-operating characteristic curve, the sensitivity and specificity for differentiating between the group with cardiac death and the group without cardiac death were 85.7% and 59.3%, respectively. Kaplan-Meier analysis revealed that the higher NLR group (≥3.3) had a significantly higher cardiac death rate than the lower NLR group (<3.3) (11.1% versus 1.4%, log-rank: P < 0.0001). This value was more useful in patients with heart failure (NT-proBNP ≥ 300ng/L) or myocardial injury (hs-cTnT ≥ 100ng/L). CONCLUSIONS: The outcomes of the current study demonstrate that high NLR is a predictor of cardiac death after PCI, especially in patients with heart failure or myocardial injury.
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Linfocitos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Neutrófilos/metabolismo , Fragmentos de Péptidos/metabolismo , Intervención Coronaria Percutánea/mortalidad , Troponina T/metabolismo , Anciano , Anciano de 80 o más Años , Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , República de Corea/epidemiologíaRESUMEN
BACKGROUND: High C-reactive protein (CRP) and mean platelet volume (MPV) levels are associated with poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to evaluate the relationship between CRP level or MPV and infarct transmurality in patients with STEMI. METHODS: We retrospectively reviewed CRP level, MPV, and infarct transmurality in 112 STEMI patients who were assessed with contrast-enhanced cardiac magnetic resonance imaging. RESULTS: When the cut-off peak CRP level and MPV were set at 2.35 mg/dl and 7.3 fl using receiver operating characteristic curves analysis, the sensitivity was 67.3/69.2% and specificity was 76.7/76.7% for differentiating between the groups with and those without transmural involvement. Peak CRP level, MPV, peak creatine kinase-MB (CK-MB) level, and peak high-sensitivity cardiac troponin T (hs-cTnT) level had comparable predictive values for transmural involvement (area under the curve, 0.749, 0.761, 0.680, and 0.696, respectively). High peak CRP level and MPV were independent predictors of transmural involvement after adjusting for the peak CK-MB level, peak hs-cTnT level, baseline thrombolysis in myocardial infarction flow grade, and left ventricular ejection fraction (odds ratio: 5.16/5.42, 95% confidence interval: 1.84-14.50/2.03-14.47, P = 0.002/0.001, respectively) in the logistic regression analysis. CONCLUSION: The results of this study show that peak CRP level and MPV are predictive markers for transmural involvement. Their predictive power for transmural involvement is independent of and comparable to that of peak CK-MB and hs-cTnT levels.
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Proteína C-Reactiva/metabolismo , Volúmen Plaquetario Medio , Miocardio/patología , Infarto del Miocardio con Elevación del ST/sangre , Anciano , Estudios de Cohortes , Medios de Contraste , Creatina Quinasa/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/métodos , Valor Predictivo de las Pruebas , Curva ROC , Infarto del Miocardio con Elevación del ST/cirugía , Estadísticas no Paramétricas , Troponina TRESUMEN
This study was designed to establish the relationship of high-sensitivity C-reactive protein (hsCRP) and mean platelet volume (MPV) with the development of adverse outcomes after percutaneous coronary intervention (PCI). hsCRP levels and MPV were analysed in 372 patients who underwent PCI, with the primary endpoint as major adverse cardiac and cerebrovascular events (MACCE): a composite of cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), ischemic stroke and stent thrombosis. During the follow-up period (mean, 25.8 months), there were 21 cardiac deaths, 10 MIs including four stent thrombosis events, seven ischemic strokes and 29 TVRs. The hsCRP cut-off level was set at 0.31 mg/dl using the receiver operating characteristic curve to differentiate between the groups with and without MACCE. The MPV cut-off level was set at 8.00 fl by the receiver operating characteristic curve to differentiate between the groups with and without MACCE. A Kaplan-Meier analysis revealed that the high hsCRP group (≥0.31 mg/dl) had a significantly higher cardiac death and MACCE rate than the low hsCRP group (<0.31 mg/dl), and the high MPV group (>8.00âfl) had a significantly higher cardiac death and MACCE rate than the low MPV group (≤8.00 fl). Furthermore, the high hsCRP and MPV groups were significantly associated with an increased risk of MACCE. These results show that hsCRP and MPV are predictive markers after PCI for MACCE; they are also additively associated with a higher risk of MACCE.
Asunto(s)
Proteína C-Reactiva/metabolismo , Volúmen Plaquetario Medio/métodos , Intervención Coronaria Percutánea/métodos , Anciano , Protocolos Clínicos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Enterococcus faecalis is a Gram-positive, commensal bacterium that lives in the gastrointestinal tracts of humans and other mammals. It causes severe infections because of high antibiotic resistance. E. faecalis can endure extremes of temperature and pH. Acyl carrier protein (ACP) is a key element in the biosynthesis of fatty acids responsible for acyl group shuttling and delivery. In this study, to understand the origin of high thermal stabilities of E. faecalis ACP (Ef-ACP), its solution structure was investigated for the first time. CD experiments showed that the melting temperature of Ef-ACP is 78.8 °C, which is much higher than that of Escherichia coli ACP (67.2 °C). The overall structure of Ef-ACP shows the common ACP folding pattern consisting of four α-helices (helix I (residues 3-17), helix II (residues 39-53), helix III (residues 60-64), and helix IV (residues 68-78)) connected by three loops. Unique Ef-ACP structural features include a hydrophobic interaction between Phe(45) in helix II and Phe(18) in the α1α2 loop and a hydrogen bonding between Ser(15) in helix I and Ile(20) in the α1α2 loop, resulting in its high thermal stability. Phe(45)-mediated hydrophobic packing may block acyl chain binding subpocket II entry. Furthermore, Ser(58) in the α2α3 loop in Ef-ACP, which usually constitutes a proline in other ACPs, exhibited slow conformational exchanges, resulting in the movement of the helix III outside the structure to accommodate a longer acyl chain in the acyl binding cavity. These results might provide insights into the development of antibiotics against pathogenic drug-resistant E. faecalis strains.
Asunto(s)
Proteína Transportadora de Acilo/química , Proteína Transportadora de Acilo/metabolismo , Enterococcus faecalis/metabolismo , Proteína Transportadora de Acilo/genética , Cristalografía por Rayos X , Enterococcus faecalis/química , Enterococcus faecalis/genética , Calor , Enlace de Hidrógeno , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Estabilidad Proteica , Estructura Secundaria de ProteínaRESUMEN
Phytoncide, nanochemicals extracted from Chamaecyparis obtusa (C. obtusa), is reported to possess many pharmacological activities including immunological stimulating, anti-cancer, antioxidant, and antiinflammatory activities. However, the effect of phytoncide in vascuar diseases, especially on the behavior of vascular smooth muscle cells, has not yet been clearly elucidated. Therefore, in the present study, we investigated the effects of 15 kinds of phytoncide by various extraction conditions from C. obtusa on the proliferation and migration in rat aortic smooth muscle cells (RAoSMCs). First of all, we determined the concentration of each extracts not having cytotoxicity by MTT assay. We observed that the proliferation rate measured using BrdU assay was significantly reduced by supercritical fluid, steam distillation, Me-OH, and hexane extraction fraction in order with higher extent, respectively. Moreover, the treatment of above nanofractions inhibit the migration of RAoSMCs by 40%, 60%, and 30%, respectively, both in 2-D wound healing assay and 3-D boyden chamber assay. Immunoblot revealed that the phosphorylated levels of Akt and ERK were significantly reduced in nanofractions treated RAoSMCs. Taken together, these data suggest that phytoncide extracted from C. obtusa inhibits proliferation and migration in RAoSMCs via the modulation of phosphorylated levels of Akt and ERK. Therefore, phytoncide nanomolecules might be a potential therapeutic approach to prevent or treat atheroscrelosis and restenosis.
Asunto(s)
Chamaecyparis/química , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Aorta/citología , Aorta/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Fitoquímicos/química , Extractos Vegetales/química , Ratas , Ratas Sprague-DawleyRESUMEN
The plant Dendropanax morbifera Léveille (D. morbifera), a subtropical broad-leaved evergreen tree, have been used in folk medicine for the treatment of infectious diseases, skin diseases, and other maladies. However, the effect of extracts from D. morbifera in vascuar diseases has not yet been reported. In this study, BrdU assay revealed that extracts from D. morbifera inhibit significantly the proliferation rate of Rat Aortic Smooth Muscle Cells (RAoSMCs) by -40% in treated samples compared to controls. Notably, 2-D wound healing assay and 3-D boyden chamber assay showed the significant reduction of RAoSMCs migration induced by serum in nano extracts treated groups by -50%. We further observed that the phosphorylated levels of Akt and ERK were significantly reduced by 70% in extracts treated RAoSMCs. Moreover, the expression levels of matrix metalloproteinase (MMP) 2 and 9 were significantly reduced by extracts from D. morbifera. Our results suggest that extracts from D. morbifera inhibit proliferation and migration in RAoSMCs via the modulation of phosphorylated levels of Akt and ERK. Subsequently, the reduced MMP2 and 9 expression might result to reduced migration of RAoSMCs.
Asunto(s)
Araliaceae/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Células Cultivadas , Músculo Liso Vascular/citología , Hojas de la Planta/química , Tallos de la Planta/química , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Low triiodothyronine (T3) levels and subclinical myocardial injury may be associated with adverse cardiac and cerebrovascular (CCV) events in individuals without clinically apparent coronary heart disease (CHD). The aim of this study was to determine the associations of a low T3 level and subclinical myocardial injury with the development of adverse CCV events in individuals without clinically apparent CHD. METHODS: T3 and high-sensitivity cardiac troponin T (hs-cTnT) levels were analyzed in 250 patients with chest pain free of CHD and heart failure. The primary end point was the composite of sudden cardiac death, ischemic stroke, newly developed atrial fibrillation, pericardial effusion and thrombosis. RESULTS: Throughout a mean follow-up of 15.6 months, the primary end point happened in 17 patients (6.8%). Kaplan-Meier analysis disclosed a notably higher overall occurrence rate in patients with hs-cTnT levels ≥0.014 ng/mL and in patients with T3 <60 ng/dL. An exaggerated hazard was observed in patients with combined high hs-cTnT and low T3 levels. After adjustment, the hazard ratio for overall events in patients with high hs-cTnT/low T3 versus normal hs-cTnT/T3 was 11.72 (95% confidence interval, 2.83-48.57; P = 0.001). CONCLUSIONS: In patients with chest pain without clinically obvious CHD, high hs-cTnT combined with low T3 was associated with adverse cardiac/CCV events and was an independent predictor of overall events even after adjustment. These data suggest the importance of systemic factors, such as low T3 syndrome, in the development of adverse cardiac/CCV events beyond advancing clinical atherosclerotic coronary disease in patients with chest pain.