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OBJECTIVE: The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear. METHODS: Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI. RESULTS: Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P < 0.0001) and the GRACE score (r = 0.5684, P < 0.0001). Logistic regression analysis demonstrated that increased BAFF levels were an independent risk factor for CAD (adjusted OR 1.305, 95% CI 1.078-1.580) and AMI (adjusted OR 2.874, 95% CI 1.708-4.838) after adjusting for confounding variables. Additionally, elevated BAFF levels were significantly associated with a high GRACE score (GRACE score 155 to 319, adjusted OR 4.297, 95% CI 1.841-10.030). BAFF exhibited a sensitivity of 75.0% and specificity of 71.4% in differentiating CAD patients with a high SYNTAX score, and a sensitivity of 75.5% and specificity of 72.8% in identifying AMI patients with a high GRACE score. CONCLUSION: Circulating BAFF levels serve as a valuable diagnostic marker for CAD and AMI. Elevated BAFF levels are associated with the presence and severity of these conditions, suggesting its potential as a clinically relevant biomarker in cardiovascular disease.
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Factor Activador de Células B , Biomarcadores , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Regulación hacia Arriba , Humanos , Masculino , Factor Activador de Células B/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/diagnóstico , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Anciano , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Estudios de Casos y Controles , Factores de Riesgo , Medición de Riesgo , PronósticoRESUMEN
BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear. METHODS: We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing. RESULTS: We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CamkIIδ), thus preventing the production of CaMKIIδA, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca2+ homeostasis. In line with this, we found increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKIIδA partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice. CONCLUSIONS: These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF.
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OBJECTIVES: The B cell activating factor (BAFF) is a B cell survival factor involved in atherosclerosis and ischemia-reperfusion (IR) injury. This study sought to investigate whether BAFF is a potential predictor of poor outcomes in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We prospectively enrolled 299 patients with STEMI, and serum levels of BAFF were measured. All subjects were followed for three years. The primary endpoint was major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal reinfarction, hospitalization for heart failure (HF), and stroke. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of BAFF for MACEs. RESULTS: In multivariate analysis, BAFF was independently associated with risk of MACEs (adjusted HR 1.525, 95% CI 1.085-2.145; p = 0.015) and cardiovascular death (adjusted hazard ratio [HR] 3.632, 95% confidence interval [CI] 1.132-11.650, p = 0.030) after adjustment for traditional risk factors. Kaplan-Meier survival curves demonstrated that patients with BAFF levels above the cut-off value (1.46 ng/mL) were more likely to have MACEs (log-rank p < 0.0001) and cardiovascular death (log-rank p < 0.0001). In subgroup analysis, the impact of high BAFF on MACEs development was stronger in patients without dyslipidemia. Furthermore, the C-statistic and Integrated Discrimination Improvement (IDI) values for MACEs were improved with BAFF as an independent risk factor or when combined with cardiac troponin I. CONCLUSIONS: This study suggests that higher BAFF levels in the acute phase are an independent predictor of the incidence of MACEs in patients with STEMI.
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PURPOSE: To assess predictive value of 68Ga-labeled fibroblast activation protein inhibitor-04 ([68Ga]Ga-DOTA-FAPI-04) PET/MR for late left ventricular (LV) remodeling in patients with ST-segment elevated myocardial infarction (STEMI). METHODS: Twenty-six patients with STEMI were included in the study. [68Ga]Ga-DOTA-FAPI-04 PET/MR was performed at baseline and at average 12 months after STEMI. LV remodeling was defined as >10% increase in LV end-systolic volume (LVESV) from baseline to 12 months. RESULTS: The LV remodeling group demonstrated higher [68Ga]Ga-DOTA-FAPI-04 uptake volume (UV) at baseline than the non-LV remodeling group (p < 0.001). [68Ga]Ga-DOTA-FAPI-04 UV at baseline was a significant predictor (OR = 1.048, p = 0.011) for LV remodeling at 12 months after STEMI. Compared to clinical information, MR imaging and cardiac function parameters at baseline, [68Ga]Ga-DOTA-FAPI-04 UV demonstrated better predictive ability (AUC = 0.938, p < 0.001) for late LV remodeling, with sensitivity of 100.0% and specificity of 81.3%. CONCLUSIONS: [68Ga]Ga-DOTA-FAPI-04 PET/MR is an effective tool to non-invasively quantify myocardial fibroblasts activation, and baseline [68Ga]Ga-DOTA-FAPI-04 UV may have potential predictive value for late LV remodeling.
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Infarto del Miocardio , Infarto del Miocardio con Elevación del ST , Humanos , Radioisótopos de Galio , Remodelación Ventricular , Función Ventricular Izquierda , Infarto del Miocardio/diagnóstico por imagen , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Bone is thought to be the reservoir of the human lead burden, and vitamin D is associated with bone turnover. We aimed to explore whether exposure to lower 25-hydroxy vitamin D (25(OH)D) levels was associated with higher blood lead levels (BLLs) by increasing the bone turnover rate in individuals with type 2 diabetes. METHODS: A total of 4103 type 2 diabetic men and postmenopausal women in Shanghai, China, were enrolled in 2018. Their 25(OH)D, ß-C-terminal telopeptide (ß-CTX), N-MID osteocalcin and procollagen type 1 N-peptide (P1NP) levels were detected. Their BLLs were determined by atomic absorption spectrometry. Mediation analyses were performed to identify the possible role that bone turnover played in the underlying mechanisms. RESULTS: In both the men and postmenopausal women, all three bone turnover markers were inversely associated with 25(OH)D and positively associated with the BLL (all P < 0.01) after adjusting for age, current smoking habits, metabolic parameters, duration of diabetes, vitamin D intake, and use of anti-osteoporosis medication. In the mediation analyses, none of the direct associations between 25(OH)D and BLL was significant for the three bone turnover markers, but all three bone turnover markers were found to be significant mediators of the indirect associations between 25(OH)D and BLL. CONCLUSION: The association between vitamin D and BLL was fully mediated by bone turnover markers in type 2 diabetic patients (mediation effect). This finding suggested that vitamin D may protect against blood lead exposure from the bone reservoir by decreasing bone turnover in individuals with type 2 diabetes.
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BACKGROUND: Lead (Pb) is considered an endocrine-disrupting chemical. However, few studies have investigated the effects of low-level Pb exposure on plasma glucose levels. Herein, we aimed to investigate whether low-level Pb exposure causes elevated plasma glucose levels and the possible mechanisms involved. METHODS: We conducted a cross-sectional study of 5747 participants from 16 sites in China. The participants underwent measurements of anthropometric factors, blood lead level (BLL) and fasting plasma glucose (FPG). Wistar rats were exposed to 0.05% Pb through drinking water or fed with a high-fat diet (HFD) for 28 weeks. The relevant parameters of glucose homeostasis, hepatic glucose production (HGP) and gene expression levels of hepatic gluconeogenesis enzymes, including phosphoenolpyruvate carboxy kinase (PEPCK), glucose-6-phosphatase (G6PC) and fructose-1,6-bisphosphatase (FBP1), were measured. In addition, gene expression levels of gluconeogenesis enzymes were also measured in HepG2 cells administered with different concentrations of lead acetate for 24 h. RESULTS: In humans, after adjusting for confounders, the odds of having High_FPG (≥5.6 mmol/L) were significantly increased by 25% in the participants in the fourth BLL quartile (OR 1.25, 95% CI 1.05, 1.49). In the animals exposed to 0.05% Pb, FPG, HGP and hepatic gene expression levels of PEPCK, G6PC and FBP1 were increased. In addition, the mRNA expression levels of PEPCK, G6PC and FBP1 in HepG2 cells were also increased in response to Pb exposure. CONCLUSIONS: These findings support the possibility that low-level Pb exposure may increase HGP by affecting key enzymes of hepatic gluconeogenesis, eventually resulting in impaired FPG and hyperglycemia.
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Gluconeogénesis , Plomo , Animales , Glucemia/metabolismo , China , Estudios Transversales , Ayuno , Glucosa/metabolismo , Plomo/metabolismo , Plomo/toxicidad , Hígado/metabolismo , Ratas , Ratas WistarRESUMEN
A subfamily of transcription factors known as HD-ZIP III plays distinct roles in the secondary cell wall biosynthesis, which could be attributed to the quality of cotton fiber and adaptation to drought stress. In this study, 18 HD-ZIP III genes were identified as genome wide from the upland cotton (Gossypium hirsutum). These genes are distributed on 14 different chromosomes, and all of them have undergone segmental duplications. Numerous cis-elements were identified in the promoter regions, which are related to phytohormone responses and abiotic stresses. Expression profiling of these genes by quantitative real-time (qRT)-PCR illustrated their differential spatial expression, with preferential expression in cotton fiber. Among these genes, GhHB8-5D was predicted to encode a protein that is targeted to the cell nucleus and having self-activation ability. In addition, the ectopic expression of GhHB8-5D or its synonymous mutant GhHB8-5Dm in Arabidopsis resulted in stunted plant growth, curly leaves, and twisted inflorescence stems. Microscopy examination revealed that the morphology of vascular bundles and deposition of secondary wall had substantially altered in stems, which is concomitant with the significant alteration in the transcription levels of secondary wall-related genes in these transgenic Arabidopsis. Further, ectopic expression of GhHB8-5D or GhHB8-5Dm in Arabidopsis also led to significant increase in green seedling rate and reduction in root length relative to wild type when the plants were grown under mimicked drought stress conditions. Taken together, our results may shed new light on the functional roles of GhHB8-5D that is attributable for secondary cell wall thickening in response to drought stress. Such a finding may facilitate a novel strategy for improving plant adaptations to environmental changes via regulating the biosynthesis of secondary cell wall.