Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1

Abstract

Objective-The effect of a novel small molecule plasminogen activator inhibitor (PAI-1) inhibitor on adipose tissue physiology was investigated. Methods and Results-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 IC 50 for the inhibition of PAI-1. Conclusions-Our results indicate that a small molecule inactivator of PAI-1 can neutralize glucose-stimulated increases in PAI-1in 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. Key Words: adipocyte Ⅲ diabetes Ⅲ obesity Ⅲ PAI-1 T ype 2 diabetes accounts for Ͼ90% of diabetes globally and continues to increase at epidemic proportions. 1 Cardiovascular morbidity is a major burden in patients with type 2 diabetes, and their risk of death from cardiovascular disease is increased significantly over nondiabetic subjects. 2 Aggressive treatment of both diabetes and cardiovascular disease in this population through a combination of diet, exercise, and pharmacological therapy has recently been reported to result in a 20% reduction in cardiovascular events, 3 whereas treatment of hyperglycemia alone produces less benefit. 4 Taken together, a significant number of diabetics continue to exhibit vascular disease that is refractory to current therapy. See page 2183Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), 5 and is physiologically involved in both thrombosis and atherosclerosis. 6 PAI-1 is found in the circulation of healthy individuals at low concentrations, and although it has a potential regulatory role in tumorigenesis, inflammation, and thrombosis, 7 PAI-1 is both elevated in the plasma of type 2 diabetic patients and is an important predictor of the onset of the disease. 8 The discovery that PAI-1 is synthesized by adipose tissue suggested that it represents a possible causal link between obesity and the increased atherothrombosis observed in diabetics. This hypothesis is further supported by additional studies establi...

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…This indicates PAI‐1 may play a role in glucose regulation and is consistent with previous population studies that reported positive correlations between circulating PAI‐1 and glucose levels 6, 51, 52. In addition to observational studies, experimental studies showed that PAI‐1 deficiency via genetic knock‐out or pharmacological inhibition can suppress the levels of blood glucose in mice 53, 54. MR analysis of PAI‐1 with type 2 diabetes mellitus had a consistent effect direction with what is expected based on the glucose findings, but was not significant (Table 2).…”

Gender-specific genetic associations of polymorphisms in ACE, AKR1C2, FTO and MMP2 with weight gain over a 10-year period

“…ACE converts angiotensin I into angiotensin II, and in humans, angiotensin II increases the expression of PAI-1, whereas inhibition of ACE decreases PAI-1 in plasma and tissues (Brown et al 1998(Brown et al , 1999. In the mouse, inhibition of PAI-1 has been associated with reduced weight of fat depots and adipocyte size (Crandall et al 2006). Influence of ACE on tissue plasminogen activator (tPA) has also been reported, but remains controversial (Brown et al 1999).…”

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

“…Although an inhibitor for PAI-1 that neutralizes the activity of both PAI-1 in complex with VN and of free PAI-1 may yield the most effective inhibition, it is still possible that selective inhibition of free PAI-1 could provide therapeutic benefit. Several studies with inhibiting antibodies and small molecules against PAI-1 have shown effects in different animal models of fibrinolysis (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). We are not aware of a PAI-1 inhibitor that has been tested in patients, but the low molecular weight PAI-1 inhibitor PAI-749 (diaplasinin) has been tested ex vivo in human blood using the Badimon chamber and was found not to have an effect on in vitro or ex vivo thrombus formation or fibrinolysis in the presence or absence of tPA (43,44).…”