Masayuki Koyama

Circulating Levels of Fatty Acid-Binding Protein Family and Metabolic Phenotype in the General Population

Objective 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. Methods 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. Results 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. Conclusions 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.

Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation.

Background Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. Methods We first examined serum FABP4 concentrations in 18 normotensives (NT) and 30 nontreated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin-sensitivity index, the M value, determined by the hyperinsulinemic–euglycemic clamp technique. In the second study, we determined FABP4 levels in 30 young NT men with or without a family history of hypertension (FH+ and FH–, respectively; n = 15 each). Results Serum FABP4 level was significantly higher in the EHT-R than in the NT, whereas elevation of FABP4 level in the EHT-S was not statistically significant. FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides and negatively correlated with the M value. FABP4 level was an independent predictor of mean arterial pressure after adjustment of age, gender, and adiposity. The FH+ group had a significantly lower level of M value and higher level of FABP4 than did the FH– group, and FABP4 concentration was an independent determinant of the M value. Conclusions FABP4 contributes to blood pressure elevation and atherogenic metabolic phenotype in hypertensives, and the elevation of FABP4 is predisposed by a family history of hypertension.

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

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.

Angiotensin II receptor activation in youth triggers persistent insulin resistance and hypertension—a legacy effect?

Although the involvement of angiotensin II (Ang II) in insulin resistance and hypertension has been established, the temporal relationships between Ang II receptor activation and changes in insulin sensitivity and blood pressure are not clear. To better understand this issue, we infused rats with Ang II (200 ng kg−1 min−1) or vehicle for 4 weeks and assessed the residual effects after the discontinuation of the infusion on blood pressure, insulin sensitivity and tissue parameters of inflammation. Four weeks after the discontinuation of the Ang II infusion, the blood pressure was higher by 12.8 mm Hg, and insulin sensitivity as determined by a euglycemic hyperinsulinemic glucose clamp was reduced (glucose infusion rate: 11.1±0.7 vs. 17.6±0.5 mg kg−1 min−1) in the Ang II-treated group compared with controls. The persistent hypertension and insulin resistance were associated with greater than two-fold increases in macrophage chemoattractant protein-1, tumor necrosis factor-α and thiobarbituric acid-reactive substrates in the soleus muscle. Furthermore, total and activated forms of Rac-1, a regulatory subunit of the NADPH oxidase complex, were increased by 144±14% and 277±82%, respectively, in the skeletal muscle of Ang II-treated rats. These residual effects after Ang II infusion were all attenuated by the co-administration of tempol, a free radical scavenger, or candesartan with Ang II. The effects of candesartan were not mimicked by hydralazine at an equidepressant dose. These findings suggest that Ang II receptor activation in youth triggers the upregulation of inflammatory cytokines and the production of reactive oxygen species, thereby inducing later insulin resistance and hypertension.

Everolimus-responsive dilated cardiomyopathy in tuberous sclerosis.

Masayuki Koyama1, Toshiyuki Yano2*, Keisuke Kikuchi3, and Tetsuji Miura2 Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro 080-0016, Japan; Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo 060-8543, Japan; and Department of Pathology, Obihiro Kosei Hospital, Obihiro 080-0016, Japan * Corresponding author. Tel: +8111 611 2111, Fax: +81 11 644 7958, Email:tyano@sapmed.ac.jp

Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study

Background/Aims: Relationships between the number of anti-thrombosis agents, clinical benefits and adverse events in hemodialysis (HD) patients are unclear. Methods: All patients on HD in 22 institutes (n = 1,071) were enrolled and followed up for 3 years. After exclusion of patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204), mortality rate and ischemic and hemorrhagic events were compared between different regimens of anti-thrombosis agents. Results: The use of dual or triple antiplatelet (AP) agents (HR:2.03, 95% CI:1.01-4.13, p = 0.04) and the combination of an AP agent and warfarin (WF) (HR:4.84, 95%CI 1.96-11.96, p < 0.001) were associated with an increase in hemorrhagic events compared with no use of anti-thrombosis agents. No anti-thrombosis regimen was associated with a significant change in risk of ischemic stroke. The use of dual or triple AP agents, but not WF, was associated with an increase in cardiovascular mortality (HR:2.48, 95% CI:1.24-4.76, p = 0.01). Conclusion: A significant increase in hemorrhagic events by the use of dual or more AP agents and by co-administration of an AP agent and WF in patients on HD should be considered in planning their anti-thrombosis regimen.

Lethal heart failure with anti-mitochondrial antibody: an arrhythmogenic right ventricular cardiomyopathy mimetic

A 60-year-old woman with heart failure and no family history of cardiomyopathy/sudden death was referred to our hospital. Echocardiography revealed large pericardial effusion and thinning of akinetic right ventricular free wall ( Panel s A and B ). Serum biochemistry showed low level of free thyroxine with elevation of thyroid-stimulating hormone level, elevated …

198 ELEVATION OF SERUM FATTY ACID-BINDING PROTEIN 4 LEVEL IN YOUNG NORMOTENSIVE MEN WITH A FAMILY HISTORY OF HYPERTENSION

Objectives: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), mainly expressed in adipocytes, has shown to be secreted from adipocytes, and the elevated concentration of FABP4 is associated with obesity and insulin resistance. It has also been demonstrated that normotensive offspring of patients with essential hypertension have decreased insulin sensitivity compared to subjects without a family history of hypertension. However, little is known about the association between FABP4 concentration and insulin sensitivity in young normotensives with and without a family history of hypertension. Methods: We determined the M value as an insulin sensitivity index determined by the hyperinsulinemic-euglycemic clamp technique and circulating levels of FABP4, glucose, insulin, and lipid variables in 30 young normotensive men with or without a family history of hypertension (FH+ and FH-, respectively; n = 15 each). Results: The FH+ group had significantly lower M value (218.0 ± 17.0 vs. 299.9 ± 13.7 mg/m2/min) and higher level of FABP4 (15.1 ± 1.0 vs. 11.4 ± 0.9 ng/ml) than did the FH- group. In analysis using data from both FH+ and FH-, FABP4 concentration was positively correlated with BMI (r = 0.45) and triglycerides (r = 0.44) and negatively correlated with the M value (r = -0.50) and HDL cholesterol (r = -0.46). Stepwise regression analysis using the correlated parameters and presence of family history of hypertension showed that the M value was independently adopted as a determinant of FABP4 concentration. Conclusions: Vera Farah2 - The reduction of insulin sensitivity coupled to increase in FABP4 concentration might precede the development of hypertension in young men with a family history of hypertension.

199 SERUM FABP4 (A-FABP/AP2) AND FABP5 (E-FABP/MAL1) AS POSSIBLE BIOMARKERS OF INSULIN RESISTANCE AND CORONARY ATHEROSCLEROSIS

Objectives: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) and 5 (FABP5/E-FABP/mal1) are expressed in both adipocytes and macrophages and paly important roles of development of insulin resistance and atherosclerosis. Recent studies have shown that elevated serum FABP4 is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the association of FABP5 concentration with insulin resistance and atherosclerosis. Methods: We determined serum levels of FABP4 and FABP5 and severity of coronary stenosis by the modified Gensinis score in coronary angiography in 34 male patients with stable angina pectoris. Results: Serum FABP5 concentration (1.2 ± 0.1 ng/ml) was about 15-fold lower than FABP4 level (18.1 ± 1.5 ng/ml). Both levels of FABP4 and FABP5 were positively correlated with age (r = 0.35, 0.42, respectively), body mass index (BMI; r = 0.42, 0.37), fasting plasma glucose (r = 0.43, 0.35), insulin (r = 0.50, 0.40) and HOMA-R (r = 0.55, 0.45) and negatively correlated with estimated glomerular filtration rate (eGFR; r = -0.34, -0.42). Multiple regression analysis showed that HOMA-R was an independent determinant of both FABP4 and FABP5 after adjustment of age, BMI, and eGFR. Coronary stenosis score was not correlated with age, blood pressure, HOMA-R or LDL cholesterol. There was a significant correlation of coronary stenosis score with FABP4 level (r = 0.37, p = 0.003) but not with FABP5 level (r = 0.26, p = 0.138). Conclusions: Concentration of FABP4 and FABP5 might be novel biomarkers of insulin resistance. FABP4 level might additionally predict severity of coronary atherosclerosis.