The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases

Abstract

The 50 kDa glycoprotein plasminogen activator inhibitor 1 (PAI-1) is the major physiological inhibitor of tissue-type and urokinase-type plasminogen activator. These two molecules convert inactive plasminogen into its fibrin-degrading form, plasmin. Plasma and tissue concentrations of PAI-1 are extremely low under normal circumstances but increase under pathologic conditions. This increase is mediated by many factors, including reactive oxygen species. Increased PAI-1 activity is associated with an increased risk of ischemic cardiovascular events and tissue fibrosis. Whereas the antifibrinolytic property of PAI-1 derives mainly from its inhibition of serine proteases, its profibrotic actions seem to derive from a capacity to stimulate interstitial macrophage recruitment and increase transcription of profibrotic genes, as well as from inhibition of serine proteases. Despite studies in mice that lack or overexpress PAI-1, the biological effects of this molecule in humans remain incompletely understood because of the complexity of the PAI-1-plasminogen-activator-plasmin system. The cardioprotective and renoprotective properties of some currently available drugs might be attributable in part to inhibition of PAI-1. The development of an orally active, high-affinity PAI-1 inhibitor will provide a potentially important pharmacological tool for further investigation of the role of PAI-1 and might offer a novel therapeutic strategy in renal and cardiovascular diseases.

Structure-Activity Relationships of New N-Acylanthranilic Acid Derivatives as Plasminogen Activator Inhibitor-1 Inhibitors

“…This compound was prepared in 89% yield as a solid from methyl 4-aminobiphenyl-3-carboxylate (6d) 13) and diglycolic anhydride following a procedure similar to that described for the preparation of 14a, 1 1 (1H, s), 12.7 (1H, br).…”

“…amount) in THF (5 ml) was added oxalyl dichloride (414 mg,1.99 mmol) at 0°C, and the mixture was stirred at room temperature for 1 h. After evaporation of organic solvent, a solution of 4-chloroaniline (211 mg, 1.66 mmol) in DMA (5 ml) was added to the residue at 0°C, and the mixture was stirred at room temperature for 1 h. Aqueous NaHCO 3 solution was added to the reaction mixture and the resulting precipitate was collected by suction filtration and washed with water to afford 345 mg (yield 51%) of 15a as a solid, 1 1H, s).…”

“…Elevated levels of plasminogen activator inhibitor-1 (PAI-1), a serine protease which inhibits tissue-type and urokinase-type plasminogen activators (tPA and uPA, respectively), is thought to be a cause of a variety of diseases, 1) such as thrombotic diseases (e.g., brain infarction, deep vein thrombosis, etc. ), tissue fibrotic diseases (e.g., lung thrombosis, renal thrombosis, liver thrombosis etc.…”

Plasminogen Activator Inhibitor-1 Antisense Oligodeoxynucleotides Abrogate Mesangial Fibronectin Accumulation

“…PAI-1 is a 50 kD single chain glycoprotein, upregulated by various stimuli including transforming growth factor-β1 (TGF-β1), and activated and stabilized by binding to vitronectin [7][8][9][10]. In the normal human kidney, PAI-1 is undetectable in the basal level but the expression is upregulated in several acute and chronic kidney diseases [9,10] including diabetic nephropathy [11].…”

“…PAI-1 is a 50 kD single chain glycoprotein, upregulated by various stimuli including transforming growth factor-β1 (TGF-β1), and activated and stabilized by binding to vitronectin [7][8][9][10]. In the normal human kidney, PAI-1 is undetectable in the basal level but the expression is upregulated in several acute and chronic kidney diseases [9,10] including diabetic nephropathy [11]. A functional role of PAI-1 in renal diseases was established mainly by in vivo studies using PAI-1 knock out (KO) mice; renal fibrosis in crescentic glomerulonephritis [12], unilateral ureteral obstruction [13], and diabetic nephropathy [14][15][16] was attenuated in PAI-1 KO mice.…”