Plasminogen Activator Inhibitor1

Plasminogen activator inhibitor (PAI)-1 is a globular glycoprotein with a molecular weight of 50,000 and comprised of 379 amino acids in a single chain. The primary structure of PAI-1 designates it as a member of the superfamily of serine protease inhibitors (serpins), and it is structurally similar to other serpins, including angiotensinogen, antithrombin III, and a-2-antiplasmin. PAI-1 was first isolated by Van Mourik et al. (121) and has been cloned by several investigative groups (122,123).

At least three distinct conformations of the intact PAI-1 molecule have been identified. In its latent form, PAI-1 is not susceptible to cleavage by tPA nor does it form complexes with tPA. However, in its active form, it is both susceptible to cleavage and does form complexes with the tPA molecule. The active form of PAI-1 is the inhibitory form of the molecule. In its conformation, the reactive site of PAI-1 is readily accessible to cleavage by plasminogen activators; once this peptide bond is cleaved, a complex is formed between plasminogen activators and PAI-1. Thus, the active form of PAI has been appropriately termed a suicide substrate. It has a circulating half-life of approx 60 min (124).

Latent PAI-1 has been crystallized, and its structure determined; it is inactive because part of its reactive centers is inaccessible to binding. Latent conformation of PAI appears to be a preferred state, and spontaneous reversions of latent PAI to an active state have not been described. However, if latent PAI is chemically denatured and allowed to refold,

Table 8

Major inflammatory Cytokines


Cytokine cell of origin Biologic activity

IL-1 Endothelial cells

Activated macrophages IL-2 Activated T cell IL-6 Monocytes, macrophages,

T cells, endothelial cells INF-y Activated T cells

TNF-a Monocytes, macrophages

T cell activation; cytokine production

Activated natural killer cells stimulate IL-2, TNF-a Differentiatial of B cells; stimulate production of acute phase proteins and cytokines Oxygen-derived free radical production expression of MHC I and II; monocyte and macrophage activation Cytokine production; endothelial cell injury; pro-thrombotic effects, cellular proliferation

IL, interleukin; TNF-y, tumor necrosis factor a; INF-y, interferon y; and MHC, major histocompatibility complex.

a fraction of the material will resume the active conformation (125). It has been determined that most PAI-1 secreted into the blood is in the active state, although some of the PAI stored within platelets is inactive. The mechanisms responsible for activating latent PAI have not been fully described, but negatively charged phospholipids have been reported to activate the latent form of PAI in vitro (126).

The primary source of PAI-1 in the circulation is thought to be the endothelium (127); however, this is not the only synthetic site. Other sites of synthesis include the liver and vascular smooth muscle cells. Platelets store large quantities of PAI-1, which can be secreted following aggregation. Endothelial cells also have the capacity to secrete PAI-1 abluminally (128). The relative abundance of vitronectin in the suben-dothelial matrix provides a mechanism for preserving PAI-1 activity. The PAI-1-vitronectin complex may represent the physiologically relevant form of the inhibitor in the extracellular matrix.

A wide array of compounds has been found to stimulate endothelial PAI-1 production. Inflammatory cytokines, including IL-1 and TNF, can induce PAI-1 synthesis. Transforming growth factor-b, epidermal growth factor, and insulin can also stimulate PAI-1 production. Thrombin is a potent stimulus for PAI-1 in cultured endothelial cells (129).

An excess of PAI-1 reduces the efficiency of the fibrinolytic system, creating a permissive environment toward vascular thrombosis. There is compelling evidence that PAI-1 exists in excess quantities within human atherosclerotic vessels (130). Elevated levels of PAI-1 are a risk factor for both venous and arterial thrombolic events. PAI-1 excess has been identified in young survivors of acute MI (131). It has also found in excess among survivors of MI who subsequently experienced a second event (132) (Fig. 15).

Was this article helpful?

0 0
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook

Post a comment