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Cardiovasc. Med."],"abstract":"<jats:p>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-\u03b1, 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.<\/jats:p>","DOI":"10.3389\/fcvm.2021.653655","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T14:24:44Z","timestamp":1618583084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":115,"title":["A Serpin With a Finger in Many PAIs: PAI-1's Central Function in Thromboinflammation and Cardiovascular Disease"],"prefix":"10.3389","volume":"8","author":[{"given":"Gael B.","family":"Morrow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire S.","family":"Whyte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola J.","family":"Mutch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/355270a0","article-title":"Structural basis of latency in plasminogen activator inhibitor-1","volume":"355","author":"Mottonen","year":"1992","journal-title":"Nature."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.1021\/bi00178a022","article-title":"Engineering plasminogen activator inhibitor 1 mutants with increased functional stability","volume":"33","author":"Lawrence","year":"1994","journal-title":"Biochemistry."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1161\/01.RES.67.5.1281","article-title":"Studies of recombinant plasminogen activator inhibitor-1 in rabbits. 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