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A serpin with a finger in many PAIs: PAI-1’s central function in thromboinflammation and cardiovascular disease.

Morrow, Gael B.; Whyte, Claire S.; Mutch, Nicola J.


Claire S. Whyte

Nicola J. Mutch


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.


MORROW, G.B., WHYTE, C.S. and MUTCH, N.J. 2021. A serpin with a finger in many PAIs: PAI-1’s central function in thromboinflammation and cardiovascular disease. Frontiers in cardiovascular medicine [online], 8, article 653655. Available from:

Journal Article Type Review
Acceptance Date Feb 23, 2021
Online Publication Date Apr 16, 2021
Publication Date Dec 31, 2021
Deposit Date Aug 7, 2023
Publicly Available Date Aug 15, 2023
Journal Frontiers in cardiovascular medicine
Electronic ISSN 2297-055X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 8
Article Number 653655
Keywords PAI-1; Fibrinolysis; Metabolic syndrome; Obese; Diabetes; Thrombosis; Inflammation
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MORROW 2021 A serpin with a finger (VOR) (1 Mb)

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Copyright Statement
© 2021 Morrow, Whyte and Mutch. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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