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To understand why Chlamydia trachomatis (Ct) (L2/434/Bu) favors hypoxia, we examined the dynamics of infected cells using a glycolysis-related PCR array and metabolomic analysis, along with the perturbation of nucleotide synthesis. Our findings revealed that, compared to normoxia, hypoxia with infection significantly and selectively upregulates the expression of genes related to glycolysis, glycogen degradation, and the pentose phosphate pathway. Furthermore, hypoxia induced a significant decrease in metabolite levels, particularly methionine-related metabolites, independent of infection, indicating efficient metabolism under hypoxia. Additionally, the perturbation of nucleotide synthesis with adenosine derivatives impaired Ct growth. Collectively, our results suggest that Ct favors a hypoxic environment with efficient metabolism, in which Ct readily activates glycolysis responsible for stable nucleotide synthesis as well as ATP supply.
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BACKGROUND: Early detection and intervention for preclinical heart failure (HF) are crucial for restraining the potential increase in patients with HF. Thus, we designed and conducted a single-center retrospective cohort study to confirm the efficacy of B-type natriuretic peptide (BNP) for the early detection of preclinical HF in a primary care setting. METHODSâANDâRESULTS: We investigated 477 patients with no prior diagnosis of HF who were under the care of general practitioners. These patients were categorized into 4 groups based on BNP concentrations: Category 1, 0 pg/mL≤BNP≤35 pg/mL; Category 2, 35 pg/mL
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Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Atenção Primária à Saúde , Humanos , Peptídeo Natriurético Encefálico/sangue , Idoso , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Idoso de 80 Anos ou mais , Diagnóstico Precoce , Biomarcadores/sangueRESUMO
The 88thAnnual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8thto Sunday, March 10thin Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.
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BACKGROUND: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD).MethodsâandâResults: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92-139] vs. 142 [121-165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110-157] vs. 142 [123-174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman's r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76-0.96, P=0.033), whereas HDL-C was not. CONCLUSIONS: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.
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Doenças Cardiovasculares , Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Humanos , Masculino , Feminino , Lipoproteínas HDL , Doenças Cardiovasculares/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , HDL-ColesterolRESUMO
BACKGROUND: Diabetes increases the risk of heart failure (HF). 3-Hydroxyisobutyric acid (3-HIB) is a muscle-derived metabolite reflecting systemic insulin resistance. In this study, we investigated the prognostic impact of 3-HIB in patients with chronic HF.MethodsâandâResults: The KUNIUMI Registry chronic cohort is a community-based cohort study of chronic HF in Awaji Island, Japan. We analyzed the association between serum 3-HIB concentrations and adverse cardiovascular (CV) events in 784 patients from this cohort. Serum 3-HIB concentrations were significantly higher in patients with than without diabetes (P=0.0229) and were positively correlated with several metabolic parameters. According to Kaplan-Meier analysis, rates of CV death and HF hospitalization at 2 years were significantly higher among HF patients without diabetes in the high 3-HIB group (3-HIB concentrations above the median; i.e., >11.30 µmol/L) than in the low 3-HIB group (log-rank P=0.0151 and P=0.0344, respectively). Multivariable Cox proportional hazard models adjusted for established risk factors for HF revealed high 3-HIB as an independent predictor of CV death (hazard ratio [HR] 1.82; 95% confidence interval [CI] 1.16-2.85; P=0.009) and HF hospitalization (HR 1.72; 95% CI 1.17-2.53, P=0.006) in HF patients without diabetes, whereas no such trend was seen in subjects with diabetes. CONCLUSIONS: In a community cohort, circulating 3-HIB concentrations were associated with prognosis in chronic HF patients without diabetes.
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Diabetes Mellitus , Insuficiência Cardíaca , Humanos , Estudos de Coortes , Prognóstico , Insuficiência Cardíaca/etiologia , Doença Crônica , Hospitalização , Sistema de RegistrosRESUMO
Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatographyâmass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),ãhemoglobin, and lipid peroxide (LPO) {standardized ß (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.
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Cistina , Disfunção Ventricular Esquerda , Humanos , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia , Metionina , Cromatografia Líquida , Espectrometria de Massas em Tandem , Função Ventricular Esquerda , Volume Sistólico , DiástoleRESUMO
Alterations in cardiac metabolism are strongly associated with the pathogenesis of heart failure (HF). We recently reported that glutamine-dependent anaplerosis, termed glutaminolysis, was activated by H2O2 stimulation in rat cardiomyocytes, which seemed to be an adaptive response by which cardiomyocytes survive acute stress. However, the molecular mechanisms and fundamental roles of glutaminolysis in the pathophysiology of the failing heart are still unknown. Here, we treated wild-type mice (C57BL/6J) and rat neonatal cardiomyocytes (RNCMs) and fibroblasts (RNCFs) with angiotensin II (ANG II) to induce pathological cardiac remodeling. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was significantly increased in ANG II-induced mouse hearts, RNCMs and RNCFs. Unexpectedly, a GLS1 inhibitor attenuated ANG II-induced left ventricular hypertrophy and fibrosis in the mice, and gene knockdown and pharmacological perturbation of GLS1 suppressed hypertrophy and the proliferation of RNCMs and RNCFs, respectively. Using mass spectrometry (MS)-based stable isotope tracing with 13C-labeled glutamine, we observed glutamine metabolic flux in ANG II-treated RNCMs and RNCFs. The incorporation of 13C atoms into tricarboxylic acid (TCA) cycle intermediates and their derivatives was markedly enhanced in both cell types, indicating the activation of glutaminolysis in hypertrophied hearts. Notably, GLS1 inhibition reduced the production of glutamine-derived aspartate and citrate, which are required for the biosynthesis of nucleic acids and lipids, possibly contributing to the suppression of cardiac hypertrophy and fibrosis. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibition of this anaplerotic pathway could be a novel therapeutic approach for HF.NEW & NOTEWORTHY To our knowledge, this study is the first to demonstrate that increased GLS1 expression and subsequent activation of glutaminolysis are associated with exacerbation of cardiac hypertrophy and fibrosis. Inhibiting GLS1 antagonized the adverse cardiac remodeling in vitro and in vivo, partly due to reduction of glutamine-derived metabolites, which are necessary for cellular growth and proliferation. Increased glutamine utilization for anabolic reactions in cardiac cells may be related to the pathogenesis and development of HF.
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Glutaminase , Remodelação Ventricular , Animais , Glutaminase/genética , Glutaminase/metabolismo , Glutamina/metabolismo , Peróxido de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , RatosRESUMO
RATIONALE: The gene encoding TCF21 (transcription factor 21) has been linked to coronary artery disease risk by human genome-wide association studies in multiple racial ethnic groups. In murine models, Tcf21 is required for phenotypic modulation of smooth muscle cells (SMCs) in atherosclerotic tissues and promotes a fibroblast phenotype in these cells. In humans, TCF21 expression inhibits risk for coronary artery disease. The molecular mechanism by which TCF21 regulates SMC phenotype is not known. OBJECTIVE: To better understand how TCF21 affects the SMC phenotype, we sought to investigate the possible mechanisms by which it regulates the lineage determining MYOCD (myocardin)-SRF (serum response factor) pathway. METHODS AND RESULTS: Modulation of TCF21 expression in human coronary artery SMC revealed that TCF21 suppresses a broad range of SMC markers, as well as key SMC transcription factors MYOCD and SRF, at the RNA and protein level. We conducted chromatin immunoprecipitation-sequencing to map SRF-binding sites in human coronary artery SMC, showing that binding is colocalized in the genome with TCF21, including at a novel enhancer in the SRF gene, and at the MYOCD gene promoter. In vitro genome editing indicated that the SRF enhancer CArG box regulates transcription of the SRF gene, and mutation of this conserved motif in the orthologous mouse SRF enhancer revealed decreased SRF expression in aorta and heart tissues. Direct TCF21 binding and transcriptional inhibition at colocalized sites were established by reporter gene transfection assays. Chromatin immunoprecipitation and protein coimmunoprecipitation studies provided evidence that TCF21 blocks MYOCD and SRF association by direct TCF21-MYOCD interaction. CONCLUSIONS: These data indicate that TCF21 antagonizes the MYOCD-SRF pathway through multiple mechanisms, further establishing a role for this coronary artery disease-associated gene in fundamental SMC processes and indicating the importance of smooth muscle response to vascular stress and phenotypic modulation of this cell type in coronary artery disease risk.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Fator de Resposta Sérica/genética , Transativadores/genética , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação/genética , Células Cultivadas , Regulação da Expressão Gênica , Células HEK293 , Humanos , Miócitos de Músculo Liso/citologia , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Fator de Resposta Sérica/metabolismo , Transdução de Sinais/genética , Transativadores/metabolismoRESUMO
BACKGROUND: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC. METHODS: We combined RNA-sequencing, chromatin immunoprecipitation followed by sequencing, assay for transposase-accessible chromatin using sequencing, and in vitro assays in human coronary artery SMCs, with single-cell RNA-sequencing, histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease. RESULTS: Genomic studies coupled with functional assays in cultured human coronary artery SMCs revealed that AHR modulates the human coronary artery SMC phenotype and suppresses ossification in these cells. Lineage-tracing and activity-tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMCs in the atherosclerotic lesion cap. Furthermore, single-cell RNA-sequencing studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMCs expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes," were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMCs in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout in comparison with wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses. CONCLUSIONS: Overall, we conclude that AHR promotes the maintenance of lesion cap integrity and diminishes the disease-related SMC-to-chondromyocyte transition in atherosclerotic tissues.
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Vasos Coronários/patologia , Miócitos de Músculo Liso/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Fosfatase Alcalina/genética , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Condrogênese , Colágeno Tipo II/genética , Exposição Ambiental , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica , Receptores de Hidrocarboneto Arílico/genéticaRESUMO
BACKGROUND: Metabolic remodeling in cardiomyocytes is deeply associated with the pathogenesis of heart failure (HF). Glutaminolysis is an anaplerotic pathway that incorporates α-ketoglutarate (αKG) derived from glutamine into the tricarboxylic acid (TCA) cycle. It is well known that cancer cells depend on glutamine for their increased energy demand and proliferation; however, the physiological roles of glutamine metabolism in failing hearts remain unclear. OBJECTIVE: To investigate the regulatory mechanisms and biological effects of glutamine metabolism in oxidative stress-induced failing myocardium. METHODS AND RESULTS: The intracellular levels of glutamine, glutamate, and αKG were significantly decreased by H2O2 stimulation in rat neonatal cardiomyocytes (RNCMs). To better understand the metabolic flux in failing myocardium, we performed a stable isotope tracing study and found that glutaminolysis was upregulated in RNCMs under oxidative stress. Consistent with this, the enzymatic activity of glutaminase (Gls), which converts glutamine to glutamate, was augmented in RNCMs treated with H2O2. These findings suggest that glutamine anaplerosis is enhanced in cardiomyocytes under oxidative stress to compensate for the reduction of αKG. Furthermore, the inhibition of Gls reduced cardiac cell viability, ATP production, and glutathione (GSH) synthesis in RNCMs with H2O2 stimulation. Finally, we evaluated the effects of αKG on failing myocardium and observed that dimethyl α-ketoglutarate (DMKG) suppressed oxidative stress-induced cell death likely due to the enhancement of intracellular ATP and GSH levels. CONCLUSION: Our study demonstrates that under oxidative stress, glutaminolysis is upregulated to compensate for the loss of αKG and its replenishment into the TCA cycle, thereby exerting cardioprotective effects by maintaining ATP and GSH levels. Modulation of glutamine metabolism in failing hearts might provide a new therapeutic strategy for HF.
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Glutamina/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Animais Recém-Nascidos , Sobrevivência Celular , Células Cultivadas , Ciclo do Ácido Cítrico , Metabolismo Energético , Ácido Glutâmico/metabolismo , Glutaminase/metabolismo , Insuficiência Cardíaca/metabolismo , Ácidos Cetoglutáricos/metabolismo , Redes e Vias Metabólicas , Miócitos Cardíacos/citologia , Estresse Oxidativo , RatosRESUMO
Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFß pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Doença da Artéria Coronariana/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Proteína Smad3/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sítios de Ligação , Diferenciação Celular/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Epistasia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Transdução de Sinais , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: Trans-fatty acid (TFA) intake increases the risk of coronary artery disease (CAD). Our previous cross-sectional survey showed that middle-aged patients with CAD in Japan have elevated serum TFA. In this study, we longitudinally investigated whether elevated TFA is a risk factor in the secondary prevention of CAD for the same-age patients. MethodsâandâResults: A total of 112 patients (age, 21-66 years) who underwent percutaneous coronary intervention were followed up for up to 2 years. Serum elaidic acid was measured using gas chromatography/mass spectrometry as a marker of TFA intake and divided into quartiles. The primary endpoint was ischemia-driven target lesion revascularization (TLR). The hazard ratio (HR) for TLR increased significantly with higher serum elaidic acid (P<0.01). The significant positive trend remained unchanged after adjusting for conventional lipid profile and bare-metal stent usage. In contrast, although triglycerides and low-density lipoprotein cholesterol were positively correlated with elaidic acid, they were not associated with TLR. On multivariable Cox proportional hazard analysis, elevated elaidic acid was independently associated with TLR risk after adjusting for conventional coronary risks (HR, 10.7, P<0.01). CONCLUSIONS: Elevated elaidic acid is associated with higher TLR rate in middle-aged patients with CAD, suggesting that excessive TFA intake is becoming a serious health problem in Japan.
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Ácidos Oleicos/sangue , Intervenção Coronária Percutânea , Sistema de Registros , Stents , Adulto , Fatores Etários , Idoso , LDL-Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Graxos trans/efeitos adversos , Triglicerídeos/sangueRESUMO
BACKGROUND: It has previously been reported that oral administration of purified eicosapentaenoic acid (EPA) generates EPA-rich high-density lipoprotein (HDL) particles with a variety of anti-inflammatory properties. In this study, the mechanism underlying the anti-atherogenic effects of EPA-rich HDL using reconstituted HDL (rHDL) was investigated.MethodsâandâResults:rHDL was generated by the sodium cholate dialysis method, using apolipoprotein A-1 protein, cholesterol, and various concentrations of EPA-phosphatidylcholine (PC) or egg-PC. Increased EPA-PC contents in rHDL resulted in decreased particle size. Next, the effects of rHDL containing various amounts (0-100% of total PC) of EPA-PC on vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical vein endothelial cells (HUVECs) was examined. Cytokine-stimulated VCAM-1 expression was inhibited in a dose-dependent manner based on the amount of EPA-PC in rHDL. Surprisingly, the incubation of HUVECs with EPA-rich rHDL resulted in the production of resolvin E3 (RvE3), an anti-inflammatory metabolite derived from EPA. Incubation with EPA-PC alone did not adequately induce RvE3 production, suggesting that RvE3 production requires an endothelial cell-HDL interaction. The increased anti-inflammatory effects of EPA-rich HDL may be explained by EPA itself and RvE3 production. Furthermore, the increase in EPA-PC content enhanced cholesterol efflux. CONCLUSIONS: The EPA-enriched HDL particles exhibit cardioprotective properties via the production of anti-inflammatory lipid metabolites and the increase in cholesterol efflux.
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Aterosclerose/tratamento farmacológico , Ácido Eicosapentaenoico/farmacologia , Lipoproteínas HDL/farmacologia , Células Cultivadas , Colesterol/metabolismo , Ácido Eicosapentaenoico/uso terapêutico , Ácidos Graxos Insaturados/biossíntese , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Recent studies have shown that the ketone body ß-hydroxybutyrate (ßOHB) acts not only as a carrier of energy but also as a signaling molecule that has a role in diverse cellular functions. Circulating levels of ketone bodies have been previously reported to be increased in patients with congestive heart failure (HF). In this study, we investigated regulatory mechanism and pathophysiological role of ßOHB in HF. First, we revealed that ßOHB level was elevated in failing hearts, but not in blood, using pressure-overloaded mice. We also measured cellular ßOHB levels in both cardiomyocytes and non-cardiomyocytes stimulated with or without H2O2 and revealed that increased myocardial ßOHB was derived from cardiomyocytes but not non-cardiomyocytes under pathological states. Next, we sought to elucidate the mechanisms of myocardial ßOHB elevation and its implication under pathological states. The gene and protein expression levels of CoA transferase (SCOT), a key enzyme involved in ketone body oxidation, was decreased in failing hearts. In cardiomyocytes, H2O2 stimulation caused ßOHB accumulation concomitantly with SCOT downregulation, implying that the accumulation of myocardial ßOHB occurs because of the decline in its utilization. Finally, we checked the effects of ßOHB on cardiomyocytes under oxidative stress. We found that ßOHB induced FOXO3a, an oxidative stress resistance gene, and its target enzyme, SOD2 and catalase. Consequently, ßOHB attenuated reactive oxygen species production and alleviated apoptosis induced by oxidative stress. It has been reported that hyperadrenergic state in HF boost lipolysis and result in elevation of circulating free fatty acids, which can lead hepatic ketogenesis for energy metabolism alteration. The present findings suggest that the accumulation of ßOHB also occurs as a compensatory response against oxidative stress in failing hearts.
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Ácido 3-Hidroxibutírico/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Ácido 3-Hidroxibutírico/análise , Animais , Células Cultivadas , Coenzima A-Transferases/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , RatosRESUMO
Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography-mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation.
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Ácidos Graxos Ômega-3 , Humanos , Camundongos , Animais , Ácidos Graxos Ômega-3/metabolismo , Células Endoteliais/metabolismo , Norepinefrina , Remodelação Vascular , Inflamação/tratamento farmacológicoRESUMO
BACKGROUND: Although low high-density lipoprotein cholesterol (HDL-C) levels are a common metabolic abnormality associated with insulin resistance, their role in cardiovascular risk stratification remains controversial. Recently, we developed a simple, high-throughput, cell-free assay system to evaluate the "cholesterol uptake capacity (CUC)" as a novel concept for HDL functionality. In this study, we assessed the CUC in patients with hypertriglyceridemia and diabetes mellitus. METHODS: The CUC was measured using cryopreserved serum samples from 285 patients who underwent coronary angiography or percutaneous coronary intervention between December 2014 and May 2019 at Kobe University Hospital. RESULTS: The CUC was significantly lower in diabetic patients (n = 125) than in nondiabetic patients (93.0 vs 100.7â arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150â mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0â A.U., P = 0.004). Furthermore, the CUC showed a significant inverse correlation with TG, hemoglobin A1c (Hb A1c), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Finally, the HDL-C/Apolipoprotein A1 (ApoA1) ratio, calculated as a surrogate index of HDL particle size, was significantly positively correlated with the CUC (r2 = 0.49, P < 0.001), but inversely correlated with TG levels (r2 = -0.30, P < 0.001). CONCLUSIONS: The CUC decreased in patients with hypertriglyceridemia and diabetes mellitus, and HDL particle size was a factor defining the CUC and inversely correlated with TG levels, suggesting that impaired CUC in insulin-resistant states was partially due to the shift in HDL towards smaller particles. These findings provide a better understanding of the mechanisms underlying impaired HDL functionality.
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HDL-Colesterol , Hipertrigliceridemia , Resistência à Insulina , Triglicerídeos , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , HDL-Colesterol/sangue , Triglicerídeos/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Apolipoproteína A-I/sangue , Colesterol/sangue , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análiseRESUMO
We previously found a novel type of chilling injury in the leaves of rice seedlings (Oryza sativa L. cv. Akitakomachi). The damage was only observed when the roots were not chilled (10 °C/25 °C, shoots/roots), but not when the whole seedling was chilled (10 °C/10 °C). In this report, we show that the chilling injury induced by high root temperature required nitrate and potassium together with a trace amount of iron, manganese or both in the nutrient solution during the treatment, and that the injury was increased by nitrogen starvation before chilling. Both nitrate and nitrite accumulated in the 10 °C/25 °C leaves when the nutrient solution contained nitrate. The nitrate accumulation in the 10 °C/25 °C leaves was highest at the end of the first light period, and was followed by a decrease with a concomitant increase in nitrite during the first dark period. The photosynthetic electron transport was completely lost in both PSII and PSI in the 10 °C/25 °C leaves when the nutrient solution contained nitrate. However, the activities in the leaves of the 10 °C/25 °C plants treated with the nutrient solution lacking nitrate remained at approximately half those in the 10 °C/10°C leaves. The photochemical quenching of Chl fluorescence and the P700 oxidation state were also intermediate between those in the 10 °C/25 °C and 10 °C/10°C leaves of plants supplied with the complete nutrients. Thus, the chilling injury was closely linked to the accumulation of nitrate and nitrite, as well as to a malfunction of photosynthesis in the 10 °C/25 °C leaves.
Assuntos
Nitratos/metabolismo , Nitritos/metabolismo , Oryza/metabolismo , Fotossíntese , Aminoácidos/análise , Aminoácidos/metabolismo , Clorofila/metabolismo , Transporte de Elétrons , Oryza/fisiologia , Folhas de Planta/metabolismo , Folhas de Planta/fisiologia , Raízes de Plantas/metabolismo , Raízes de Plantas/fisiologia , Brotos de Planta/metabolismo , Brotos de Planta/fisiologia , Plântula/metabolismo , Plântula/fisiologia , Estresse Fisiológico , Temperatura , Xilema/metabolismo , Xilema/fisiologiaRESUMO
High-density lipoprotein (HDL) cholesterol efflux capacity (CEC), which is a conventional metric of HDL function, has been associated with coronary heart disease risk. However, the CEC assay requires cultured cells and takes several days to perform. We previously established a cell-free assay to evaluate cholesterol uptake capacity (CUC) as a novel measure of HDL functionality and demonstrated its utility in coronary risk stratification. To apply this concept clinically, we developed a rapid and sensitive assay system based on a chemiluminescent magnetic particle immunoassay. The system is fully automated, providing high reproducibility. Measurement of CUC in serum is completed within 20 min per sample without HDL isolation, a notably higher throughput than that of the conventional CEC assay. CUC decreased with myeloperoxidase-mediated oxidation of HDL or in the presence of N-ethylmaleimide, an inhibitor of lecithin: cholesterol acyltransferase (LCAT), whereas CUC was enhanced by the addition of recombinant LCAT. Furthermore, CUC correlated with CEC even after being normalized by ApoA1 concentration and was significantly associated with the requirement for revascularization due to the recurrence of coronary lesions. Therefore, our new assay system shows potential for the accurate measurement of CUC in serum and permits assessing cardiovascular health.
Assuntos
Doenças Cardiovasculares , Lipoproteínas HDL , Humanos , Doenças Cardiovasculares/diagnóstico , Reprodutibilidade dos Testes , HDL-Colesterol , ImunoensaioRESUMO
AIMS: With the rapidly increasing ageing population, heart failure is an urgent challenge, particularly in developed countries. The study aimed to investigate the main aetiologies of chronic heart failure in a super-aged society. METHODS AND RESULTS: The KUNIUMI registry chronic cohort is a community-based, prospective, observational study of chronic heart failure in Awaji Island, Japan. Inhabitants of this island aged ≥65 years accounted for 36.3% of the population. In the present study, data from patients with symptomatic heart failure were extracted from the registry. A total of 1646 patients were enrolled from March 2019 to March 2021, accounting for ~1.3% of the inhabitants of Awaji Island. We analysed 852 patients with symptomatic heart failure. The mean age was high (78.7 ± 11.1 years), with 357 patients (41.9%) being female. The proportion of women increased significantly with advancing age and constituted more than half of the patients aged 85 years and older (P < 0.01). The prevalence of atrial fibrillation, and in particular long-standing persistent atrial fibrillation, increased at 70 years of age (P < 0.01). The proportion of patients with heart failure with preserved ejection fraction increased to ~60% when age was over 75 years. Although ischaemic heart disease accounted for 35.0% of chronic heart failure aetiologies, valvular heart disease was the most common cause of chronic heart failure (49.8%). The major types of valvular heart disease were mitral regurgitation and tricuspid regurgitation (27.2% and 21.7%, respectively), both of which increased significantly with age (P < 0.01). The incidence of aortic valve stenosis increased markedly over the age of 85 years (P < 0.01). Atrial functional mitral regurgitation increased with age and was the major cause of mitral regurgitation in patients aged >75 years. Patients with atrial functional mitral regurgitation had a higher prevalence of atrial fibrillation (especially long-standing persistent atrial fibrillation) and a larger left atrial volume index when compared with patients with other types of mitral regurgitation (P < 0.001, respectively). CONCLUSIONS: The KUNIUMI registry chronic cohort showed a change in heart failure aetiology to valvular heart disease in a super-aged society. Effective and comprehensive countermeasures are required to prepare for the rapid rise in heart failure incidence in a super-aged society.
Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Doenças das Valvas Cardíacas , Insuficiência da Valva Mitral , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Fibrilação Atrial/epidemiologia , Estudos Prospectivos , Sistema de RegistrosRESUMO
Previously, it was reported that like land plants, the green alga Klebsormidium flaccidum (Streptophyta) accumulates sucrose during cold acclimation (Nagao et al. Plant Cell Environ 31:872-885, 2008), suggesting that synthesis of sucrose could enhance the freezing tolerance of this alga. Because sucrose phosphate phosphatase (SPP; EC 3.1.3.24) is a key enzyme in the sucrose synthesis pathway in plants, we analyzed the SPP gene in K. flaccidum (KfSPP, GenBank accession number AB669024) to clarify its role in sucrose accumulation. As determined from its deduced amino acid sequence, KfSPP contains the N-terminal domain that is characteristic of the L-2-haloacid-dehalogenase family of phosphatases/hydrolases (the HAD phosphatase domain). However, it lacks the extensive C-terminal domain found in SPPs of land plants. Database searches revealed that the SPPs in cyanobacteria also lack the C-terminal domain. In addition, the green alga Coccomyxa (Chlorophyta) and K. flaccidum, which are closely related to land plants, have cyanobacterial-type SPPs, while Chlorella (Chlorophyta) has a land plant-type SPP. These results demonstrate that even K. flaccidum (Streptophyta), as a recent ancestor of land plants, has the cyanobacterial-type SPP lacking the C-terminal domain. Because SPP and sucrose phosphate synthase (SPS) catalyze sequential reactions in sucrose synthesis in green plant cells and the lack of the C-terminal domain in KfSPP is predicted to decrease its activity, the interaction between decreased KfSPP activity and SPS activity may alter sucrose synthesis during cold acclimation in K. flaccidum.