Yoko Shibata

Association of heart-type fatty acid-binding protein with cardiovascular risk factors and all-cause mortality in the general population: the Takahata study.

Background Despite many recent advances in medicine, preventing the development of cardiovascular diseases remains a challenge. Heart-type fatty acid-binding protein (H-FABP) is a marker of ongoing myocardial damage and has been reported to be a useful indicator for future cardiovascular events. However, it remains to be determined whether H-FABP can predict all-cause and cardiovascular deaths in the general population. Methods and Results This longitudinal cohort study included 3,503 subjects who participated in a community-based health checkup with a 7-year follow-up. Serum H-FABP was measured in registered subjects. The results demonstrated that higher H-FABP levels were associated with increasing numbers of cardiovascular risk factors, including hypertension, diabetes mellitus, obesity, and metabolic syndrome. There were 158 deaths during the follow-up period, including 50 cardiovascular deaths. Deceased subjects had higher H-FABP levels compared to surviving subjects. Multivariate Cox proportional hazard regression analysis revealed that H-FABP is an independent predictor of all-cause and cardiovascular deaths after adjustments for confounding factors. Subjects were divided into four quartiles according to H-FABP level, and Kaplan-Meier analysis demonstrated that the highest H-FABP quartile was associated with the greatest risks for all-cause and cardiovascular deaths. Net reclassification index and integrated discrimination index were significantly increased by addition of H-FABP to cardiovascular risk factors. Conclusions H-FABP level was increased in association with greater numbers of cardiovascular risk factors and was an independent risk factor for all-cause and cardiovascular deaths. H-FABP could be a useful indicator for the early identification of high-risk subjects in the general population.

Association between plasma adiponectin levels and decline in forced expiratory volume in 1 s in a general Japanese population: the Takahata study.

Background:Adiponectin is an anti-inflammatory and cardio-protective cytokine. However, several studies have demonstrated that plasma adiponectin levels were inversely associated with pulmonary function in patients with chronic obstructive pulmonary disease, suggesting a proinflammatory or pulmonary-destructive role. It is still unclear whether adiponectin is a potent biomarker predicting declines in pulmonary function. The aim of this study was to investigate the association between adiponectin and pulmonary function among Japanese individuals who participated in an annual health check-up. Methods:Spirometry and blood sampling, including measurements of plasma adiponectin, were performed for 3,253 subjects aged 40 years or older who participated in a community-based annual health check-up in Takahata, Japan from 2004 to 2006. In 2011, spirometry was re-performed, and the data from 872 subjects (405 men and 467 women) were available for a longitudinal analysis. Results:Plasma adiponectin levels were found to be significantly associated with age, body mass index (BMI), and alanine aminotransferase (ALT), triglycerides (TG), and high-density lipoprotein-cholesterol (HDL-c) levels among both men and women in the study population. Plasma adiponectin levels were found to be associated with lifetime cigarette consumption (Brinkman index, BI) in men only. Plasma adiponectin levels were inversely correlated with forced expiratory volume in 1 s (FEV1) per forced vital capacity in both men and women. In addition, the annual change in FEV1 was inversely associated with plasma adiponectin levels in both genders. A multiple linear regression analysis revealed that this association was independent of other confounding factors such as age, BMI, BI, ALT, TG, and HDL-c. Conclusions:The results of the present study suggest that adiponectin levels are predictive of declines in FEV1 in the general population.

Slight increase in urinary albumin excretion within the normal range predicts incident hypertension in a community-based Japanese population: the Takahata study.

Recent studies have suggested that urine albumin excretion in the high normal range predicts hypertension. However, the relationship between urinary albumin excretion in spot urine and incident hypertension remains unclear in the general Japanese population. To clarify this relationship, we conducted a cohort study in a community-based population of 412 normotensive individuals without diabetes and renal insufficiency and examined the incidence of hypertension using the urinary albumin-to-creatinine ratio (UACR) at baseline. Incident hypertension was defined as new-onset systolic blood pressure ⩾140u2009mmu2009Hg and/or diastolic blood pressure ⩾90u2009mmu2009Hg and/or the use of anti-hypertensive drugs. During the follow-up period (median, 6.7 years), 133 subjects (32.3%) newly developed hypertension. The incidence of hypertension increased with an increase in baseline UACR (20.4% for UACR <5u2009mgu2009g−1, 34.0% for 5–9.9u2009mgu2009g−1 UACR and 40.4% for 10–29.9u2009mgu2009g−1, P=0.002). Multivariate logistic regression analysis, after adjustment for possible confounders, showed that UACR 5–9.9u2009mgu2009g−1 and 10–29.9u2009mgu2009g−1 were independent risks for incident hypertension compared with UACR <5u2009mgu2009g−1 (odds ratio (OR) 2.15, 95% confidence interval (CI) 1.16–4.10 and OR 2.67, 95% CI 1.36–5.38, respectively). Subgroup analysis revealed that subjects with increased UACR (⩾5u2009mgu2009g−1) had a higher risk of incident hypertension than did those with low UACR (<5u2009mgu2009g−1), irrespective of their backgrounds (age, sex, smoking, alcohol consumption, obesity and urinary sodium excretion). In conclusion, this study showed that a slight increase in urinary albumin excretion might predict incident hypertension in a community-based Japanese population.

Serum uric acid levels and mortality in the Japanese population: the Yamagata (Takahata) study

BackgroundSerum uric acid level is regulated by gender, dietary habit, genetic predisposition, and renal function, and is associated with the development of renal and cardiovascular diseases. This study prospectively investigated the association between serum uric acid levels and mortality in a community-based population.MethodsThree thousand four hundred and eighty-seven subjects regardless of the antihyperuricemic medication (45xa0% male; mean age 62xa0years old) from the Takahata town in Japan participated in this study and were followed up for 8xa0years (median 7.5xa0years). We examined the association between serum uric acid levels at baseline and the all-cause and cardiovascular mortality, respectively, in this population.ResultsOne hundred seventy-nine subjects died during the follow-up period, with 49 deaths attributed to cardiovascular causes. Kaplan–Meier analysis revealed that the all-cause mortality was significantly higher along with the increase in serum uric acid levels at baseline among female (Log-rank Pxa0<xa00.01), but not male subjects (Pxa0=xa00.97). Cox-proportional hazard model analysis with adjustment for possible confounders including age, renal function, and comorbidities revealed that hyperuricemia (uric acidxa0≥7.0xa0mg/dL) was an independent risk factor for all-cause and cardiovascular mortality, respectively, in female [hazard ratio (HR) 5.92, 95xa0% confidence interval (CI) 2.10–14.6 for all-cause mortality, and HR 10.7, 95xa0% CI 1.76–50.2 for cardiovascular mortality], but not male subjects.ConclusionHyperuricemia was an independent risk for all-cause and cardiovascular mortality in female, but not among the male subjects in a community-based population.

Reference values of MostGraph measures for middle-aged and elderly Japanese individuals who participated in annual health checkups

BACKGROUNDnThe forced oscillation technique (FOT) can measure respiratory system resistance and reactance under tidal volume respiration. MostGraph is a device that incorporates the FOT and enables the immediate, three-dimensional visualization of resistance and reactance parameters. The aim of this study was to establish MostGraph reference values for middle-aged and elderly Japanese individuals.nnnMETHODSnFrom 2004 to 2006, 3253 subjects living in Takahata, Yamagata underwent spirometry. Of these, 872 again underwent spirometry in 2011, and 784 (368 men, ages 46-89 years; 416 women, ages 47-90 years) underwent FOT examinations using MostGraph-01.nnnRESULTSnIn this study population, 19.0% of the men and 91.5% of the women were life-long never smokers. Abnormal spirometric findings were observed in 30.2% of the men and 14.6% of the women. Although the respiratory system resistance and reactance parameters obtained using MostGraph were not distributed normally, normal distribution was achieved via natural logarithm (R5, R20, Fres, and ALX), square root (R5-R20), or exponential (X5) transformation. Furthermore, the transformed values were converted back to the actual values after determining the values representing one and two standard deviations from the mean.nnnCONCLUSIONnRespiratory system resistance and reactance reference values were determined using MostGraph in middle-aged and elderly Japanese individuals who participated in annual health checkups.

Inhibition of elastase-pulmonary emphysema in dominant-negative MafB transgenic mice.

Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.

MafB enhances the phagocytic activity of RAW264.7 macrophages by promoting Fcgr3 expression.

This study was designed to investigate whether MafB influences the phagocytic activity of macrophages by modulating the expression of the Fc receptors for IgG (FcγRs), Fcgr2b and Fcgr3. In macrophages, FcγRs are critical for the phagocytosis of opsonized pathogens. Of these receptors, Fcgr3 has been shown to play an important role in host defense. As a model to evaluate the mechanism by which MafB influences phagocytosis, we utilized a macrophage cell-line that constitutively expresses a MafB-specific short hairpin (sh)RNA (RAW264.7-MafB-shRNA). Specifically, the levels of Fc receptor mediated-phagocytosis and the levels of FcγRs surface expression were evaluated by flow cytometry analysis, while quantitative real-time PCR analysis was utilized to examine the mRNA expression levels of FcγRs. Compared to the control cell population, RAW264.7-MafB-shRNA cells exhibited significant reductions in Fcgr3 expression and Fc receptor-mediated phagocytosis, but no difference in Fcgr2b expression. Likewise, there was markedly decreased surface expression of Fcgr3 antigen, but not Fcgr2b antigen, in RAW264.7-MafB-shRNA, compared to the control cells. Meanwhile, the observed reduction in the phagocytic activity of the MafB-shRNA-expressing cells was attenuated by ectopic expression of Fcgr3. Together, the results presented here indicate that MafB influences the phagocytic activity of macrophages by promoting Fcgr3, but not Fcgr2b, expression.

Low arterial blood oxygenation is associated with calcification of the coronary arteries in patients with chronic obstructive pulmonary disease.

BACKGROUNDnCigarette smoking is a well-known major cause of both chronic obstructive pulmonary disease (COPD) and atherosclerosis. However, few studies have investigated the correlation between COPD and coronary atherosclerosis.nnnMETHODSnWe recruited 54 patients with stable COPD (51 men, 3 women) but without angina symptoms. Arterial blood gas analyses were performed, pulmonary function was assessed, and calcification of the coronary arteries was evaluated by computed tomography (CT).nnnRESULTSnCalcification of the coronary arteries was noted in 25 patients. There were no significant differences in age, body mass index, respiratory function, and levels of low-density lipoprotein cholesterol, hemoglobin A1c, glucose, or C-reactive protein between patients with or without calcification of the coronary arteries. Arterial blood oxygenation was significantly lower in patients with calcification of the coronary arteries. On both univariate and multivariate analyses, low arterial blood oxygenation was an independent risk factor for calcification of the coronary arteries.nnnCONCLUSIONSnIn patients with COPD, low arterial blood oxygenation was strongly associated with calcification of the coronary arteries and may be a significant predictor of cardiovascular disease.

SCGB3A2 Inhibits Acrolein-Induced Apoptosis through Decreased p53 Phosphorylation

Chronic obstructive pulmonary disease (COPD), a major global health problem with increasing morbidity and mortality rates, is anticipated to become the third leading cause of death worldwide by 2020. COPD arises from exposure to cigarette smoke. Acrolein, which is contained in cigarette smoke, is the most important risk factor for COPD. It causes lung injury through altering apoptosis and causes inflammation by augmenting p53 phosphorylation and producing reactive oxygen species (ROS). Secretoglobin (SCGB) 3A2, a secretory protein predominantly present in the epithelial cells of the lungs and trachea, is a cytokine-like small molecule having anti-inflammatory, antifibrotic, and growth factor activities. In this study, the effect of SCGB3A2 on acrolein-related apoptosis was investigated using the mouse fibroblast cell line MLg as the first step in determining the possible therapeutic value of SCGB3A2 in COPD. Acrolein increased the production of ROS and phosphorylation of p53 and induced apoptosis in MLg cells. While the extent of ROS production induced by acrolein was not affected by SCGB3A2, p53 phosphorylation was significantly decreased by SCGB3A2. These results demonstrate that SCGB3A2 inhibited acrolein-induced apoptosis through decreased p53 phosphorylation, not altered ROS levels.

Role of chemokine C-C motif ligand-1 in acute and chronic pulmonary inflammations.

BackgroundChemokine C-C motif ligand 1 (CCL1) accumulates C-C motif chemokine receptor 8 positive leukocytes to the inflammatory sites. Single-nucleotide polymorphisms in the chemokine CCL1 gene are associated with exacerbation of chronic obstructive lung disease. However, it is unclear whether CCL1 has immunomodulatory functions during pulmonary inflammation. This study aimed to elucidate this issue using newly generated transgenic mice that express CCL1 in the lungs (SPC-CCL1 mice).MethodsTo evaluate the phenotypes of these mice, lung section and bronchoalveolar lavage (BAL) fluid analyses were performed. We intratracheally administered lipopolysaccharide (LPS) or Mycobacterium bovis as a model of acute or chronic lung inflammation, respectively.ResultsNo histological differences were observed between lung tissue from SPC-CCL1 Tg and wild-type mice in the resting condition and after LPS administration. In the resting condition, the total BAL cell concentration was lower in SPC-CCL1 Tg mice than in wild-type mice (Pxa0=xa00.0097). Flow cytometric analyses showed that SPC-CCL1 Tg mice had fewer F4/80-positive cells than wild-type mice (Pxa0=xa00.0278). After intratracheal LPS administration, CCL1 overexpression changed neither the total numbers nor population of BAL cells. After mycobacterial administration, pulmonary granuloma formation was significantly enhanced. The degree of Immunostaining for endoplasmic reticulum to nucleus signaling 1, a molecule associated with granuloma formation and endoplasmic reticulum stress, was significantly enhanced in the granuloma regions of SPC-CCL1 mice treated with Mycobacterium, compared to those of wild-type mice.ConclusionsCCL1 overexpression in the lungs did not change the acute inflammatory response induced by LPS, but enhanced granuloma formation after mycobacterial treatment, possibly through enhancing endoplasmic reticulum stress.