A Serpin With a Finger in Many PAIs: PAI-1's Central Function in Thromboinflammation and Cardiovascular Disease

Abstract

Plasminogen activator inhibitor 1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. PAI-1 is the principal inhibitor of the plasminogen activators, tissue plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Turbulence in the levels of PAI-1 tilts the balance of the hemostatic system resulting in bleeding or thrombotic complications. Not surprisingly, there is strong evidence that documents the role of PAI-1 in cardiovascular disease. The more recent uncovering of the coalition between the hemostatic and inflammatory pathways has exposed a distinct role for PAI-1. The storm of proinflammatory cytokines liberated during inflammation, including IL-6 and TNF-α, directly influence PAI-1 synthesis and increase circulating levels of this serpin. Consequently, elevated levels of PAI-1 are commonplace during infection and are frequently associated with a hypofibrinolytic state and thrombotic complications. Elevated PAI-1 levels are also a feature of metabolic syndrome, which is defined by a cluster of abnormalities including obesity, type 2 diabetes, hypertension, and elevated triglyceride. Metabolic syndrome is in itself defined as a proinflammatory state associated with elevated levels of cytokines. In addition, insulin has a direct impact on PAI-1 synthesis bridging these pathways. This review describes the key physiological functions of PAI-1 and how these become perturbed during disease processes. We focus on the direct relationship between PAI-1 and inflammation and the repercussion in terms of an ensuing hypofibrinolytic state and thromboembolic complications. Collectively, these observations strengthen the utility of PAI-1 as a viable drug target for the treatment of various diseases.

Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism

“…Adjustment for BMI was carried out due to the association of obesity with both plasma PAI-1 levels 10,11 and VTE, 3,4 making it an important potential confounder for the association between PAI-1 and VTE. Analyses were additionally adjusted for CRP because inflammation, as reflected by CRP levels, is reported to be associated with PAI-1 levels 16,24 and VTE. 30,31 P values for linear trend across increasing tertiles of PAI-1 levels were estimated.…”

“…[18][19][20][21][22][23] These inconsistencies could be due to limited statistical power of some studies, differences in study design and clinical characteristics of participants, poor harmonization between PAI-1 assays, and the biology of PAI-1. For instance, as a positive acute phase protein, PAI-1 levels can be affected by a variety of conditions associated with an inflammatory state, 16,24 which may be especially challenging to deal with in case-control studies as it may induce reverse causation. Given that attenuated fibrinolysis is considered an important feature in obesity, 11 clarification of the role of PAI-1 as a risk factor for VTE may provide novel insights into biological pathways that could serve as potential targets for VTE prevention in obese subjects.…”

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

“…For example, vitronectin functions as an acute-phase molecule, exhibiting increased tissue levels under inflammatory conditions [ 102 , 103 , 104 ], which also increase with age [ 101 ]. Likewise, PAI-1 is dramatically elevated in the proinflammatory state, as in tissue injury, sepsis, and inflammation [ 105 ], and is also considered a key marker and mediator of senescence [ 106 ], a hallmark of ageing [ 101 ]. Thus, VTN and PAI-1 gene expression may be upregulated cooperatively by age-related mechanisms, but without a mutual dependency of each other.…”

Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration

“…Although PAI-1 protein levels did not entirely follow expression of Pai-1 mRNA, it was clear that fat-1 mice express far less Pai-1 than their WT counterparts. The most thoroughly characterized function of PAI-1 is in regulating fibrin formation ( Morrow et al, 2021 ), giving it a central role in liver fibrosis ( Wang et al, 2007 ), which is a hallmark of later stages of ALD. However, PAI-1 can also serve as a chemoattractant for and apoptosis inhibitor of neutrophils ( Marshall et al, 2003 ; Zmijewski et al, 2011 ).…”