Biochemical properties of plasminogen activator inhibitor-1

Abstract

PAI-1 is a Mr ~50,000 glycoprotein, which is the primary physiological inhibitor of the two plasminogen activators uPA and tPA. PAI-1 belongs to the serpin protein family. Studies of PAI-1 have contributed significantly to the elucidation of the protease inhibitory mechanism of serpins, which is based on a metastable native state becoming stabilised by insertion of the RCL into the central beta-sheet A and formation of covalent complexes with target proteases. In PAI-1, this insertion can occur in the absence of the protease, resulting in generation of a so-called latent, inactive form of the protein. PAI-1, in its active state, also binds to the extracellular protein vitronectin. When in complex with its target proteases, it binds with high affinity to endocytosis receptors of the low density receptor family.

Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding

“…The catalytic activity of uPA is mainly inhibited by the serpin plasminogen activator inhibitor-1 (PAI-1), thus making plasminogen activation a highly controlled temporary and localized event. Inhibition of uPA by PAI-1 results in the formation of an inactive covalently linked uPA-PAI-1 complex, which is internalized together with uPAR by endocytosis receptors of the low-density lipoprotein receptor family, leading to lysosomal degradation of uPA-PAI-1 and recycling of free uPAR to the cell surface (for review, see Dupont et al 2009). Beside being a protease, uPA is involved in molecular interactions independent of its proteolytic activity.…”

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

“…On the surface of the clot, the inactive proenzyme plasminogen is converted to the active enzyme plasmin, which degrades fibrin into soluble fibrin degradation products. The serine proteases that activate plasminogen into plasmin are tissue-type plasminogen activator (tPA) 2 and urokinase-type plasminogen activator (uPA) (2). Inhibition of the fibrinolytic system in vivo may occur either at the level of plasmin by ␣ 2 -antiplasmin or ␣ 2 -macroglobulin.…”

Inhibitory effect of water extractive components from heshiko and narezushi on plasma PAI-1 activity in rats

“…Heshiko and narezushi extract were confirmed not to affect tPA activity by direct mixing (data not shown), therefore, these results indicated that the heshiko and narezushi extracts inhibit PAI-1 directly by promoting PAI-1 latency, since latent PAI-1 cannot inhibit tPA. 2,5,6 However, the extract components are ingested and absorbed in the alimentary canal prior to inhibition of plasma PAI-1. Therefore, the PAI-1 inhibitory activity of these extracts (as shown in Fig.…”

“…PAI-1 loses its tPA inhibitory activity by inserting the RCL into the inside of the PAI-1 molecule as the latent state. [2][3][4][5][6] It is already known that small molecules including peptides can inhibit PAI-1 activity by entering into the cleft of the PAI-1 molecule as a mock substance. [25][26][27][28] As the extracts from heshiko and narezushi contain a large amount of peptides, 19,20 therefore, direct PAI-1 inhibition by heshiko and narezushi extracts is proposed as a possible mechanism to explain the reduced PAI-1 activity of rats shown in Table 3.…”

“…2,5,6 PAI-1 is a serine protease inhibitor that is mainly secreted from the endothelium, and PAI-1 expression and activity are regulated by various factors in the circulatory system. 1 For example, angiotensin II, a product of the renin-angiotensin system involved in the regulation of blood pressure, triggers the expression of PAI-1.…”