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Publications (2)10.98 Total impact

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    ABSTRACT: The effect of a novel small molecule plasminogen activator inhibitor (PAI-1) inhibitor on adipose tissue physiology was investigated. In human preadipocyte cultures, PAI-039 inhibited both basal and glucose-stimulated increases in active PAI-1 antigen, yet had no effect on PAI-1 mRNA, suggesting a direct inactivation of PAI-1. Differentiation of human preadipocytes to adipocytes was associated with leptin synthesis, which was significantly reduced in the presence of PAI-039, together with an atypical adipocyte morphology characterized by a reduction in the size and number of lipid containing vesicles. In a model of diet-induced obesity, pair-fed C57 Bl/6 mice administered PAI-039 in a high-fat diet exhibited a dose-dependent reduction in body weight, epididymal adipose tissue weight, adipocyte volume, and circulating plasma active PAI-1. Plasma glucose, triglycerides, and leptin were also significantly reduced in drug-treated mice, and concentrations of PAI-039 associated with these physiological effects were near the in vitro IC50 for the inhibition of PAI-1. Our results indicate that a small molecule inactivator of PAI-1 can neutralize glucose-stimulated increases in PAI-1 in human preadipocyte cultures, reduce adipocyte differentiation, and prevent the development of diet-induced obesity. These data suggest the pharmacological inhibition of PAI-1 could be beneficial in diseases associated with expansion of adipose tissue mass.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2006; 26(10):2209-15. DOI:10.1161/01.ATV.0000235605.51400.9d · 6.00 Impact Factor
  • Thrombosis and Haemostasis 06/2004; 91(5):1051-2. DOI:10.1267/THRO04051051 · 4.98 Impact Factor