Serum Levels of Adipocyte Fatty Acid-Binding Protein Are Associated with the Severity of Coronary Artery Disease in Chinese Women

BACKGROUND: Adipocyte fatty acid-binding protein (A-FABP) has been described as a novel adipokine, playing an important role in the development of metabolic syndrome, type 2 diabetes and atherosclerosis. In this study, we investigated the relationship between serum levels of A-FABP and the presence and severity of coronary artery disease (CAD) in Chinese subjects. METHODOLOGY/PRINCIPAL FINDINGS: Circulating A-FABP level was determined by ELISA in 341 Chinese subjects (221 men, 120 women) who underwent coronary angiography. A-FABP levels in patients with CAD were significantly higher compared with non-CAD subjects (P = 0.029 in men; P = 0.031 in women). Serum A-FABP increased significantly in multi-vessel diseased patients than in non-CAD subjects (P = 0.011 in men, P = 0.004 in women), and showed an independent correlation with coronary atherosclerosis index (standardized β = 0.173, P = 0.025). In multiple logistic regression analysis, serum A-FABP was an independent risk factor for CAD in women (OR = 5.637, 95%CI: 1.299-24.457, P = 0.021). In addition, amino terminal pro-brain natriuretic peptide (NT-proBNP) was demonstrated to be positively and independently correlated with A-FABP (standardized β = 0.135, P = 0.027). CONCLUSIONS/SIGNIFICANCE: Serum A-FABP is closely associated with the presence and severity of CAD in Chinese women

Distinct contractile systems for electromechanical and pharmacomechanical coupling in smooth muscle

Electromechanical coupling by KCl depolarization of bladder preparations elicits an initial phasic and subsequent tonic contraction. Using a smooth-muscle myosin heavy chain (SM-MyHC) knock-out mouse model we could previously demonstrate, that phasic and tonic contraction of intact neonatal bladder preparations could be elicited through the recruitment of SM-MyHC and non-muscle myosin heavy chains (NM-MyHC), respectively. Inhibition of myosin light chain kinase (MLCK) by ML-7 eliminated the phasic contraction of wild-type (+/+), rather than tonic contraction of neonatal bladder strips prepared from both +/+ and homozygous SM-MyHC knock-out (-/-) mice. Pharmacomechanical coupling upon PDBu-induced activation of protein kinase C of neonatal bladder preparations elicited tonic contraction of both +/+ and -/- murine. We suggest that: i) electromechanical coupling activates both SM-MyHC and NM-MyHC systems via a ML-7 sensitive and insensitive pathway, respectively. ii) Pharmacomechanical coupling recruits part of the NM-MyHC system rather than SM-MyHC

Human adipocyte-derived factors directly inhibit cardiac contraction

Obesity is a major risk factor for metabolic syndrome and cardiovascular disorders. Obesity related heart disease is the most serious complication of human obesity. Despite several investigations the pathophysiological mechanisms involved remain unclear. Latest studies have emphasized the importance of adipose tissue as a highly endocrine organ which releases a wide variety of biological active substances. In this context we have recently showed that adipose tissue exerts highly potent cardiodepressant activity with an acute effect directly on cardiomyocytes contraction, thus explaining the tight association between obesity and heart failure. Further experiments led to the assumption that the activity is a protein, but some well-known adipocyte-derived proteins could be excluded to be responsible for the effect on cardiomyocytes. In the present study we investigated the production/secretion of this adipocyte-derived negative inotropic activity in more detail

Lipoproteins and Hedgehog signalling - possible implications for the adrenal gland function.

Metabolic syndrome is a common metabolic disorder that is associated with an increased risk of type 2 diabetes and cardiovascular diseases. Disturbances in adrenal steroid hormone production significantly contribute to the development of this disorder. Therefore, it is extremely important to fully understand the mechanisms governing adrenal gland function, both in physiological and pathological conditions

BMS309403 directly suppresses cardiac contractile function

BMS309403, a substance used as an inhibitor of adipocyte fatty acid-binding protein, has been suggested as a new therapeutic agent for treating type 2 diabetes mellitus and atherosclerosis; however, little is known about its possible side effects. The present study investigates the effects of BMS309403 on the cardiovascular system. We used isolated perfused heart preparations and single cardiomyocytes from adult rats for contractile analysis. The Ca(2+) sensitivity of the myofilaments was investigated by using porcine cardiac skinned muscle fibers. BMS309403 induced a negative effect on the contractility of isolated perfused hearts leading to heart arrest without interfering in the electrocardiographic activity, suggesting electromechanical dissociation. Experiments with isolated cardiomyocytes showed that BMS309403 had a direct biphasic inhibitory effect on cardiomyocyte contraction, at higher concentrations by attenuating Ca(2+) levels. This negative inotropic effect does not result from a direct effect on the myofilaments. BMS309403 has an acute cardiac depressant effect in vitro. The potential therapeutic applicability of this compound requires additional consideration

Adipocyte-derived factors suppress heart contraction

Background: Obesity is strongly associated with cardiovascular diseases including systemic hypertension, coronary artery disease and heart failure. Despite several investigations the pathophysiological mechanisms involved remain unclear. We have previously shown that adipose tissue exerts a highly potent activity with an acute depressant effect on cardiomyocytes, thus suggesting direct involvement of adipose tissue in the development of heart dysfunction. Objective and Design: This study investigates the effects of adipocyte factors obtained from subcutaneous adipose tissue on the whole cardiac function by using isolated perfused rat hearts in a Langendorff mode. We recorded changes in coronary flow, developed isovolumetric left ventricular pressure, contraction rate and relaxation rate. Results: We observed a significant decrease in heart contractility parameters as well as in coronary flow within a few seconds of incubation with adipocyte factors. The cardiodepressant effects could not be blocked by the nonselective cyclooxygenase-inhibitor indomethacin. Human adipocytes release tumor necrosis factor-alpha, interleukin-6 (IL-6) and IL-1beta into extracellular medium. These cytokines were tested for their potential effect but were, however, not responsible for the cardiodepressant effect observed. Conclusion: These data indicate that human adipocytes secrete factors with a strong acute depressant effect on cardiac force generation and coronary flow due to contraction of the coronary vessels, thus suggesting a direct role of adipose tissue in the pathogenesis of cardiac dysfunction

Human adipocytes attenuate cardiomyocyte contraction: characterization of an adipocyte-derived negative inotropic activity

The causal relationship between obesity and heart failure is broadly acknowledged; however, the pathophysiological mechanisms involved remain unclear. In this study we investigated whether human adipocytes secrete cardioactive substances that may affect cardiomyocyte contractility. We cultivated adipocytes obtained from human white adipose tissue and incubated isolated rat adult cardiomyocytes with adipocyte-conditioned or control medium. This is the first report to demonstrate that human adipocytes exhibit cardiodepressant activity with a direct and acute effect on cardiomyocyte contraction. This adipocyte-derived negative inotropic activity directly depresses shortening amplitude as well as intracellular systolic peak Ca2+ in cardiomyocytes within a few minutes. The adipocyte-derived cardiodepressant activity was dose-dependent and was completely blunted by heating or by trypsin digestion. Filtration of adipocyte-conditioned medium based on molecular mass characterized the cardiodepressant activity at between 10 and 30 kDa. In summary, adipose tissue exerts highly potent activity with an acute depressant effect directly on cardiomyocytes, which may well contribute to increased heart failure risk in overweight patients