Fatty acid-binding proteins (FABPs) are a family of 14-15-kDa proteins, and some FABPs have been to be used as biomarkers of tissue injury by leak from cells. However, recent studies have shown that ...FABPs can be secreted from cells into circulation. Here we examined determinants and roles of circulating FABPs in a general population.
From the database of the Tanno-Sobetsu Study, a study with a population-based cohort design, data in 2011 for 296 subjects on no medication were retrieved, and FABP1~5 in their serum samples were assayed.
Level of FABP4, but not the other isoforms, showed a gender difference, being higher in females than in males. Levels of all FABPs were negatively correlated with estimated glomerular filtration rate (eGFR), but a distinct pattern of correlation with other clinical parameters was observed for each FABP isoform; significant correlates were alanine aminotransferase (ALT), blood pressure (BP), and brain natriuretic peptide (BNP) for FABP1, none besides eGFR for FABP2, age, BP, and BNP for FABP3, age, waist circumference (WC), BP, BNP, lipid variables, high-sensitivity C-reactive protein (hsCRP), and HOMA-R for FABP4, and age, WC, BP, ALT, BNP, and HOMA-R for FABP5. FABP4 is the most strongly related to metabolic markers among FABPs. In a multivariate regression analysis, FABP4 level was an independent predictor of HOMA-R after adjustment of age, gender, WC, BP, HDL cholesterol, and hsCRP.
Each FABP isoform level showed a distinct pattern of correlation with clinical parameters, although levels of all FABPs were negatively determined by renal function. Circulating FABP4 appears to be a useful biomarker for detecting pre-clinical stage of metabolic syndrome, especially insulin resistance, in the general population.
Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and elevated circulating FABP4 level is associated with obesity-mediated metabolic phenotype. We systematically ...investigated roles of FABP4 in the development of coronary artery atherosclerosis.
First, by immunohistochemical analyses, we found that FABP4 was expressed in macrophages within coronary atherosclerotic plaques and epicardial/perivascular fat in autopsy cases and macrophages within thrombi covering ruptured coronary plaques in thrombectomy samples from patients with acute myocardial infarction. Second, we confirmed that FABP4 was secreted from macrophages and adipocytes cultured in vitro. Third, we investigated the effect of exogenous FABP4 on macrophages and human coronary artery-derived smooth muscle cells and endothelial cells in vitro. Treatment of the cells with recombinant FABP4 significantly increased gene expression of inflammatory markers in a dose-dependent manner. Finally, we measured serum FABP4 level in the aortic root (Ao-FABP4) and coronary sinus (CS-FABP4) of 34 patients with suspected or known coronary artery disease. Coronary stenosis score assessed by the modified Gensini score was weakly correlated with CS-FABP4 but was not correlated with Ao-FABP4. A stronger correlation (r=0.59, P<0.01) was observed for the relationship between coronary stenosis score and coronary veno-arterial difference in FABP4 level, (CS-Ao)-FABP4, indicating local production of FABP4 during coronary circulation in the heart. Multivariate analysis indicated that (CS-Ao)-FABP4 was an independent predictor of the severity of coronary stenosis after adjustment of conventional risk factors.
FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.
Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate ...adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositol-requiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH2-terminal kinase and eukaryotic translation initiation factor-2α in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH.
High-risk coronary plaques have certain morphological characteristics. Thus, comprehensive assessment is needed for the risk stratification of plaques in patients with coronary artery disease. ...Integrated backscatter intravascular ultrasound (IB-IVUS) has been used successfully used to evaluate the tissue characteristics of coronary plaques; however, the mechanical properties of plaques have been rarely assessed. Therefore, we developed Speckle-tracking IVUS (ST-IVUS) to evaluate the mechanical properties of coronary plaque. This study aimed to evaluate the relation between the tissue characteristics of coronary plaques using IB-IVUS and their mechanical properties using ST-IVUS. We evaluated 95 non-targeted plaques in 95 patients undergoing elective percutaneous coronary intervention to the left anterior descending artery. We set regions of interest (ROIs) in the cross-sectional images of coronary plaques where we divided 120 degree plaques into four quadrants (every 30 degrees), with the center at the area of maximum atheroma thickness. We measured relative calcification area (%CA, relative fibrous area (%FI) and relative lipid pool area (%LP) in a total of 380 ROIs. In ST-IVUS analysis, we measured strain in the circumferential direction of the lumen area (LA strain: %), the external elastic membrane area strain (EEM strain: %), and strain in the radial direction (radial strain: %). On global cross-sectional area IB-IVUS analysis, the %CA was 1.2 ± 1.2%; the %FI was 49.0 ± 15.9%, and the %LP was 49.7 ± 16.5%. In ST-IVUS analysis, the LA strain was 0.67 ± 0.43%; the EEM strain was 0.49 ± 0.33%, and the radial strain was 2.02 ± 1.66%. On regional analysis, the %LP was not associated with the LA strain (
r
= − 0.002
p
= 0.97), the EEM strain (
r
= − 0.05
p
= 0.35), or with the radial strain (
r
= − 0.04
p
= 0.45). These trends were seen between the %FI and the LA strain (
r
= 0.02
p
= 0.74), the %FI and the EEM strain (
r
= 0.05
p
= 0.35), and the %FI and the radial strain (
r
= 0.04
p
= 0.50). A significant correlation was only observed between the %CA and the LA strain (
r
= − 0.15
p
= 0.0038). Our findings indicate that the associations between mechanical properties and tissue characteristics lacked statistical significance, more often than not, and that it is necessary to evaluate the mechanical properties as well as plaque characteristics for risk stratification of coronary plaques.
Objective
Fatty acid‐binding protein 4 (FABP4) is expressed in adipocytes, and elevated plasma FABP4 level is associated with obesity‐mediated metabolic phenotype. Postprandial regulation and ...secretory signaling of FABP4 has been investigated.
Methods
Time courses of FABP4 levels were examined during an oral glucose tolerance test (OGTT; n = 53) or a high‐fat test meal eating (n = 35). Effects of activators and inhibitors of adenyl cyclase (AC)‐protein kinase A (PKA) signaling and guanylyl cyclase (GC)‐protein kinase G (PKG) signaling on FABP4 secretion from mouse 3T3‐L1 adipocytes were investigated.
Results
FABP4 level significantly declined after the OGTT or a high‐fat meal eating, while insulin level was increased. Treatment with low and high glucose concentration or palmitate for 2 h did not affect FABP4 secretion from 3T3‐L1 adipocytes. FABP4 secretion was increased by stimulation of lipolysis using isoproterenol, a β3‐adrenoceptor agonist (CL316243), forskolin, dibutyryl‐cAMP and atrial natriuretic peptide, and the induced FABP4 secretion was suppressed by insulin or an inhibitor of PKA (H‐89), PKG (KT5823) or hormone sensitive lipase (CAY10499).
Conclusions
FABP4 is secreted from adipocytes in association with lipolysis regulated by AC‐PKA‐ and GC‐PKG‐mediated signal pathways. Plasma FABP4 level declines postprandially, and suppression of FABP4 secretion by insulin‐induced anti‐lipolytic signaling may be involved in this decline in FABP4 level.
Tissue characterization plays an important role in the development of acute coronary syndromes. iMap is an intravascular ultrasound (IVUS) tissue characterization system that provides useful ...information by reconstructing color-coded maps. Mechanical properties due to dynamic mechanical stress during a cardiac cycle may also trigger vulnerable plaque. Speckle tracking IVUS (ST-IVUS) has been introduced to observe plaque behavior in relation to mechanical properties. We report the case of an 84-year-old woman with stable coronary artery disease who underwent percutaneous coronary intervention, at which time IVUS demonstrated mainly three low echoic areas like lipid pools with thick fibrous caps. Pathological evaluation with iMap revealed that one low echoic area was occupied with necrotic tissue and that the other two areas occupied fibrotic. Although those tissue characterizations were different, they showed similar stretching behavior at systole by ST-IVUS which depicted plaque behavior from IVUS images using a color mapping. The mechanical properties of individual coronary plaques may differ depending on the tissue disposition. It is necessary to consider mechanical properties using ST-IVUS as well as to evaluate tissue characterization in plaque risk stratification.
The impact of real-time remote cardiac rehabilitation (CR) on health and disability-related outcomes and its correlation with physical function are unknown. We compared the effectiveness of real-time ...remote CR with that of hospital-based CR on physical function improvement and physical functions of improvement (Δ) to clarify the relationship between health and disability at baseline.
Patients with cardiovascular diseases (CVDs) were enrolled (n = 38) in this quasi-randomised controlled trial and underwent 4 weeks of hospital-based CR, followed by 12 weeks of remote or hospital-based CR based on quasi-randomised allocation. Patients were assessed at baseline and after 12 weeks of remote or hospital-based CR using the shortened version of the World Health Organization (WHO) Quality of Life scale (WHOQOL-BREF) for subjective satisfaction, WHO Disability Assessment Schedule (WHODAS2.0-J) for objective performance, and cardiopulmonary exercise test for physical function and peak oxygen uptake (peak VO
). The trends in measured variables from baseline to the post-CR stage were analysed.
Sixteen patients (mean age, 72.2 ± 10.4 years) completed remote CR, and 15 patients (mean age, 77.3 ± 4.8 years) completed hospital-based CR. The post-CR physical function differed significantly between the groups (Δ
VO
, 2.8 ± 3.0 versus 0.84 ± 1.8 mL·min
·kg
; p < 0.05). The differences in post-CR changes in the WHOQOL-BREF scores between the groups were insignificant. The post-CR changes in the WHODAS2.0-J scores were significantly lower in the remote CR group than in the hospital-based CR group (ΔWHODAS2.0-J score, -8.56 ± 14.2 versus 2.14 ± 7.6; p < 0.01). Forward multiple stepwise regression analysis using overall data showed that the intervention method (β = 0.339, p < 0.05), baseline cognition (β = - 0.424, p < 0.05), and social interaction level (β = 0.658, p < 0.01; WHODAS2.0-J) were significant independent contributors to Δpeak VO
(r
= 0.48, F = 8.13, p < 0.01).
Remote CR considerably improved physical function and objective performance in patients with CVDs. Remote CR can be used to effectively treat stable patients who cannot visit hospitals.
This interventional trial was registered at the UMIN-CTR registry (trial title: Development of remote programme for cardiac rehabilitation using wearable electrocardiograph; trial ID: UMIN000041746; trial URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046564 ; registration date: 2020/09/09).
Visit-to-visit variability in systolic blood pressure (VVV-SBP) has been associated with increased cardiac events. Hence, volume analysis by two-dimensional speckle-tracking echocardiography (2-DSTE) ...allows physicians to easily measure phasic left atrial (LA) function. However, the relationship of VVV-SBP and functional deformation of the left atrium with patients’ clinical outcome is unclear. The aim of the study was to investigate the relationship between phasic LA function and VVV-SBP. The subjects were 70 male participants in whom 2-DSTE was performed to measure blood pressure at health check-ups every year for 5 years. The standard deviation of systolic blood pressure (SBP) was calculated to assess VVV-SBP. The average SBP (Ave-SBP) was also assessed. Total emptying function (EF) (reservoir function), passive EF (conduit function), and active EF (booster pump function) of the left atrium were calculated to evaluate phasic LA function by 2-DSTE. The Pearson correlation, simple regression analysis, and multivariate logistic regression analysis were used in data analysis. Participants’ mean age was 50 ± 10 years, and 16 participants had hypertension. VVV-SBP correlated with total EF (
r
= – 0.30,
p
= 0.014) and active EF (
r
= – 0.35,
p
= 0.003). There was no correlation between the standard deviation of SBP and passive EF (
r
= – 0.10,
p
= 0.39). Ave-SBP had no significant relationship with total EF (
r
= – 0.06,
p
= 0.62), passive EF (
r
= – 0.08,
p
= 0.50), or active EF (
r
= – 0.03,
p
= 0.78). Active EF was also associated with VVV-SBP in multiple regression analysis. The active EF was significantly decreased in the highest quartile of VVV-SBP. Despite the small sample size of our study, the VVV-SBP showed a relationship with the phasic LA function. Our findings suggest that high VVV-SBP is noted to be associated with cardiovascular risk including a deterioration of LA function in clinical practice.
Background
Fatty acid‐binding protein 4 (FABP4) is expressed in adipocytes, macrophages, and endothelial cells of capillaries but not arteries. FABP4 is secreted from adipocytes in association with ...lipolysis, and an elevated circulating FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the link between FABP4 and endovascular injury. We investigated the involvement of ectopic FABP4 expression in endothelial cells in neointima hyperplasia after vascular injury.
Methods and Results
Femoral arteries of 8‐week‐old male mice were subjected to wire‐induced vascular injury. After 4 weeks, immunofluorescence staining showed that FABP4 was ectopically expressed in endothelial cells of the hyperplastic neointima. Neointima formation determined by intima area and intima to media ratio was significantly decreased in FABP4‐defficient mice compared with that in wild‐type mice. Adenovirus‐mediated overexpression of FABP4 in human coronary artery endothelial cells (HCAECs) in vitro increased inflammatory cytokines and decreased phosphorylation of nitric oxide synthase 3. Furthermore, FABP4 was secreted from HCAECs. Treatment of human coronary smooth muscle cells or HCAECs with the conditioned medium of Fabp4‐overexpressed HCAECs or recombinant FABP4 significantly increased gene expression of inflammatory cytokines and proliferation‐ and adhesion‐related molecules in cells, promoted cell proliferation and migration of human coronary smooth muscle cells, and decreased phosphorylation of nitric oxide synthase 3 in HCAECs, which were attenuated in the presence of an anti‐FABP4 antibody.
Conclusions
Ectopic expression and secretion of FABP4 in vascular endothelial cells contribute to neointima formation after vascular injury. Suppression of ectopic FABP4 in the vascular endothelium would be a novel strategy against post‐angioplasty vascular restenosis.
Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP or aP2, is secreted from adipocytes in association with lipolysis as a novel adipokine, and elevated serum FABP4 level is associated ...with obesity, insulin resistance, and atherosclerosis. However, little is known about the modulation of serum FABP4 level by therapeutic drugs. Sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases glucagon-like peptide 1 (GLP-1), was administered to patients with type 2 diabetes (n = 24) for 12 weeks. Treatment with sitagliptin decreased serum FABP4 concentration by 19.7% (17.8 ± 1.8 vs. 14.3 ± 1.5 ng/ml, P < 0.001) and hemoglobin A1c without significant changes in adiposity or lipid variables. In 3T3-L1 adipocytes, sitagliptin or exendin-4, a GLP-1 receptor agonist, had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by sitagliptin, which was not mimicked by exendin-4. Treatment with recombinant DPP-4 increased gene expression and long-term secretion of FABP4, and the effects were cancelled by sitagliptin. Furthermore, knockdown of DPP-4 in 3T3-L1 adipocytes decreased gene expression and long-term secretion of FABP4. In conclusion, sitagliptin decreases serum FABP4 level, at least in part, via reduction in the expression and consecutive secretion of FABP4 in adipocytes by direct inhibition of DPP-4.
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