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1.
Circ J ; 88(5): 732-739, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38369348

RESUMO

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.Methods and Results: 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/mL200 pg/mL. There was a marked and statistically significant increase in the prevalence of preclinical HF with increasing BNP categories: 19.9%, 57.9%, 87.5%, and 96.0% in Categories 1, 2, 3, and 4, respectively. Compared with Category 1, the odds ratio of preclinical HF in Categories 2, 3, and 4 was determined to be 5.56 (95% confidence interval [CI] 3.57-8.67), 23.70 (95% CI 8.91-63.11), and 171.77 (95% CI 10.31-2,861.93), respectively. CONCLUSIONS: Measuring BNP is a valuable tool for the early detection of preclinical HF in primary care settings. Proactive testing in patients at high risk of HF could play a crucial role in addressing the impending HF pandemic.


Assuntos
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/sangue
2.
Circ J ; 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39019582

RESUMO

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.

3.
Circ J ; 87(6): 806-812, 2023 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-36436874

RESUMO

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).Methods and Results: 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.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Humanos , Masculino , Feminino , Lipoproteínas HDL , Doenças Cardiovasculares/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , HDL-Colesterol
4.
Circ J ; 88(1): 110-116, 2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-37967948

RESUMO

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.Methods and Results: 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.


Assuntos
Diabetes Mellitus , Insuficiência Cardíaca , Humanos , Estudos de Coortes , Prognóstico , Insuficiência Cardíaca/etiologia , Doença Crônica , Hospitalização , Sistema de Registros
5.
Heart Vessels ; 38(12): 1422-1430, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37620665

RESUMO

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 chromatography‒mass 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), hemoglobin, 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.


Assuntos
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 , Diástole
6.
Am J Physiol Heart Circ Physiol ; 322(5): H749-H761, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35275762

RESUMO

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.


Assuntos
Glutaminase , Remodelação Ventricular , Animais , Glutaminase/genética , Glutaminase/metabolismo , Glutamina/metabolismo , Peróxido de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , Ratos
7.
Biochem Biophys Res Commun ; 534: 687-693, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33213841

RESUMO

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.


Assuntos
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 , Ratos
8.
Circ J ; 85(10): 1860-1868, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-33678754

RESUMO

BACKGROUND: Few registries have provided precise information concerning incidence rates for acute heart failure syndrome (AHFS) in Japan.Methods and Results:All hospitals with acute care beds in Awaji Island participated in the Kobe University heart failure registry in Awaji Medical Center (KUNIUMI Registry), a retrospective, population-based AHFS registration study, enabling almost every patient with AHFS in Awaji Island to be registered. From 1 January 2015 to 31 December 2017, 743 patients with de novo AHFS had been registered. Mean age was 82.1±11.5 years. Using the general population of Japan as of 2015 as a standard, age- and sex-adjusted incidence rates for AHFS were 133.8 per 100,000 person-years for male and 120.0 for female. In 2015, there were an estimated 159,702 new-onset patients with AHFS, which was predicted to increase to 252,153 by 2040, and reach a plateau. The proportion of patients aged >85 years accounted for 42.6% in 2015, which was predicted to increase up to 62.5% in 2040. The proportion of patients with heart failure with preserved ejection fraction was estimated at 52.0% in 2015, which was predicted to increase gradually to 57.3% in 2055. CONCLUSIONS: The present analysis suggested that the number of patients with de novo AHFS keeps increasing with progressive aging in Japan. Establishment of countermeasures against the expanding burden of HF is urgently required.


Assuntos
Insuficiência Cardíaca , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Incidência , Japão/epidemiologia , Masculino , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Síndrome
9.
Circ J ; 83(5): 1032-1038, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30867359

RESUMO

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. Methods and Results: 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.


Assuntos
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/sangue
10.
Arterioscler Thromb Vasc Biol ; 37(9): 1667-1673, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28705794

RESUMO

OBJECTIVE: Recent genome-wide association studies newly identified the human KIAA1462 gene as a new locus for coronary artery disease. However, the function of the gene product, named JCAD (junctional protein associated with coronary artery disease), is unknown. Because JCAD is expressed at cell-cell junctions in endothelial cells, we hypothesized and tested whether JCAD regulates angiogenic processes in vitro and in vivo. APPROACH AND RESULTS: Cell culture experiments revealed impaired angiogenic ability (proliferation, migration, and cord formation) by the knockdown of JCAD with siRNA (P<0.05 versus control siRNA). We have generated mice lacking JCAD (mKIAA1462-/-) by gene-targeted deletion of JCAD to address in vivo angiogenic function. mKIAA1462-/- mice did not show morphological differences in development of retinal vasculature. Ex vivo aortic ring model demonstrated impaired neovascularization in aorta from mKIAA1462-/- mice than control wild-type mice (P<0.05). Tumor growth was assessed by monitoring tumor volume after the subcutaneous injection of melanoma, LLC (Lewis lung carcinoma), and E0771 cells into the mice. mKIAA1462-/- mice exhibited significantly smaller tumor volume compared with wild-type mice (P<0.001). Histological assessment of the tumor exhibited less smooth muscle actin-positive neovascularization determined by CD31-positive vascular structure in tumor of mKIAA1462-/- mice than wild-type mice, indicating that knockdown of JCAD inhibited the vascular maturation in pathological angiogenic process. CONCLUSIONS: These in vitro and in vivo studies suggest that JCAD has a redundant functional role in physiological angiogenesis but serves a pivotal role in pathological angiogenic process after birth.


Assuntos
Moléculas de Adesão Celular/metabolismo , Células Endoteliais/metabolismo , Junções Intercelulares/metabolismo , Neovascularização Patológica , Neovascularização Fisiológica , Neovascularização Retiniana , Animais , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Movimento Celular , Proliferação de Células , Células Cultivadas , Genótipo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Técnicas de Cultura de Tecidos , Transfecção , Carga Tumoral
11.
Circ J ; 82(2): 596-601, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28652532

RESUMO

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.Methods and Results: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.


Assuntos
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/metabolismo
12.
Circ J ; 83(1): 182-192, 2018 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-30487369

RESUMO

BACKGROUND: Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). CONCLUSIONS: Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.


Assuntos
Bifidobacterium , Escherichia coli , Microbioma Gastrointestinal , Insuficiência Cardíaca , Shigella , Idoso , Idoso de 80 Anos ou mais , Bifidobacterium/classificação , Bifidobacterium/isolamento & purificação , Escherichia coli/classificação , Escherichia coli/isolamento & purificação , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/microbiologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Shigella/classificação , Shigella/isolamento & purificação
13.
Circ Res ; 117(6): 513-24, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26208651

RESUMO

RATIONALE: Accelerated arterial stiffening is a major complication of diabetes mellitus with no specific therapy available to date. OBJECTIVE: The present study investigates the role of the osteogenic transcription factor runt-related transcription factor 2 (Runx2) as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes mellitus. METHODS AND RESULTS: Using a murine model of type 2 diabetes mellitus (db/db mice), we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae, as well as in thoracic aortic samples from patients with type 2 diabetes mellitus. Vascular smooth muscle cell-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that expression of Runx2 in diabetes mellitus is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter. CONCLUSIONS: In conclusion, this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes mellitus, promoting arterial stiffness irrespective of calcification.


Assuntos
Aorta/metabolismo , Aorta/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Rigidez Vascular/fisiologia , Idoso , Animais , Células Cultivadas , Feminino , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Fatores de Transcrição/biossíntese
14.
Circulation ; 131(20): 1783-95, 2015 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-25904646

RESUMO

BACKGROUND: Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. METHODS AND RESULTS: Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. CONCLUSIONS: The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Rigidez Vascular , Adulto , Idoso , Envelhecimento/patologia , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Humanos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Elastase Pancreática/toxicidade , Estresse Mecânico , Adesivos Teciduais , Ultrassonografia
15.
Biochem Biophys Res Commun ; 475(4): 322-8, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27216458

RESUMO

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.


Assuntos
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 , Ratos
16.
Circ J ; 79(9): 2017-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26166015

RESUMO

BACKGROUND: Adverse effects of dietary intake of trans-fatty acids (TFA) on the incidence of coronary artery disease (CAD) are well recognized in Western countries. The risk of TFA, however, has not been well clarified in Japan. We investigated the association of serum TFA concentration with serum lipid profile, coronary risk factors, and prevalence of CAD. METHODS AND RESULTS: A total of 902 patients, who were hospitalized at Kobe University Hospital from July 2008 to March 2012 and gave written informed consent, were enrolled in this study. Among them, 463 patients had CAD, and 318 patients had metabolic syndrome (MetS). Serum TFA, elaidic acid (trans-9-C18:1) and linolelaidic acid (trans-9, 12-C18:2), were measured on gas chromatography/mass spectrometry. Serum TFA level had a positive correlation with body mass index, waist circumference, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B48, and an inverse correlation with age and high-density lipoprotein cholesterol. Fasting serum TFA, by age quartile in the young generation with CAD and/or MetS, was higher than that in patients without CAD and/or MetS. On multivariate logistic regression, TFA was identified as a CAD risk after adjustment for classical risk factors. CONCLUSIONS: Serum TFA concentration was elevated in young patients with CAD and/or MetS. Diet-derived TFA may cause a serious health problem, particularly in the young generation in Japan.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/induzido quimicamente , Doença da Artéria Coronariana/epidemiologia , Gorduras na Dieta/efeitos adversos , Ácidos Graxos trans/sangue , Fatores Etários , Idoso , HDL-Colesterol/sangue , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Ácido Oleico/sangue , Ácidos Oleicos , Prevalência
17.
Circ J ; 79(5): 1000-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25912562

RESUMO

BACKGROUND: Large earthquakes have been associated with cardiovascular disease (CVD) mortality. In Japan, the 1995 Great Hanshin-Awaji (H-A) Earthquake was an urban-underground-type earthquake, whereas the 2011 Great East Japan (GEJ) Earthquake was an ocean-trench type. In the present study, we examined how these different earthquake types affected CVD mortality. METHODS AND RESULTS: We examined death certificate data from 2008 to 2012 for 131 municipalities in Iwate, Miyagi, and Fukushima prefectures (n=320,348) and from 1992 to 1996 for 220 municipalities in Hyogo, Osaka, and Kyoto prefectures (n=592,670). A Poisson regression model showed significant increases in the monthly numbers of acute myocardial infarction (AMI)-related deaths (incident rate ratio [IRR] GEJ=1.34, P=0.001; IRR of H-A=1.57, P<0.001) and stroke-related deaths (IRR of GEJ=1.42, P<0.001; IRR of H-A=1.33, P<0.001) after the earthquakes. Two months after the earthquakes, AMI deaths remained significant only for H-A (IRR=1.13, P=0.029). When analyzing the standardized mortality ratio (SMR) after the earthquakes using the Cochran-Armitage trend test, seismic intensity was significantly associated with AMI mortality for 2 weeks after both the GEJ (P for trend=0.089) and H-A earthquakes (P for trend=0.005). CONCLUSIONS: Following the GEJ and H-A earthquakes, there was a sharp increase in CVD mortality. The effect of the disaster was sustained for months after the H-A earthquake, but was diminished after the GEJ Earthquake.


Assuntos
Terremotos/mortalidade , Infarto do Miocárdio/mortalidade , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Estudos Retrospectivos
18.
Arterioscler Thromb Vasc Biol ; 33(1): e1-e10, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23162013

RESUMO

OBJECTIVE: Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear. METHODS AND RESULTS: Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model. CONCLUSIONS: These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Apoptose , Doenças das Artérias Carótidas/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/deficiência , Músculo Liso Vascular/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adolescente , Adulto , Idoso , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Transplante de Medula Óssea , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/prevenção & controle , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Neointima , Elastase Pancreática , Fenótipo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Tolueno/análogos & derivados , Tolueno/farmacologia , Transfecção , Proteína Supressora de Tumor p53/antagonistas & inibidores
19.
Sci Rep ; 14(1): 4178, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378892

RESUMO

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.


Assuntos
Ácidos Graxos Ômega-3 , Humanos , Camundongos , Animais , Ácidos Graxos Ômega-3/metabolismo , Células Endoteliais/metabolismo , Norepinefrina , Remodelação Vascular , Inflamação/tratamento farmacológico
20.
J Appl Lab Med ; 9(4): 728-740, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38574000

RESUMO

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 100.7 arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150 mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0 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.


Assuntos
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/análise
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