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PAI-1 in Diabetes: Pathophysiology and Role As a Therapeutic Target

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PAI-1 in Diabetes: Pathophysiology and Role As a Therapeutic Target International Journal of Molecular Sciences Review PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target Rawan Altalhi 1,2, Nikoletta Pechlivani 2 and Ramzi A. Ajjan 2,* 1 Biochemistry Department, Faculty of Science, Jeddah University, Jeddah 23235, Saudi Arabia; [email protected] 2 Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds LS2 9JT, UK; [email protected] * Correspondence: [email protected] Abstract: Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce Citation: Altalhi, R.; Pechlivani, N.; vascular complications in diabetes. Ajjan, R.A. PAI-1 in Diabetes: Pathophysiology and Role as a Keywords: plasminogen activator inhibitor 1 (PAI-1); PAI-1 inhibitors; diabetes; hypofibrinolysis; Therapeutic Target. Int. J. Mol. Sci. cardiovascular disease; therapeutics 2021, 22, 3170. https://doi.org/ 10.3390/ijms22063170 Academic Editor: Manfredi Rizzo 1. Introduction Received: 25 February 2021 Cardiovascular disease (CVD) remains the primary cause of death in individuals with Accepted: 17 March 2021 diabetes and it also results in significant morbidity, thus compromising quality of life [1]. Published: 20 March 2021 The Framingham Heart Study has shown a 2–3-fold excess in risk of coronary artery disease (CAD), stroke, heart failure, and death from CVD among subjects with diabetes compared Publisher’s Note: MDPI stays neutral to individuals with normal glucose metabolism [2]. with regard to jurisdictional claims in Acute vascular occlusion is usually due to the formation of an obstructive thrombus published maps and institutional affil- in a diseased blood vessel. Diabetes is characterised by early and more severe atheroscle- iations. rosis being responsible for the high rate of vascular occlusive events in this population. Moreover, diabetes is associated with a thrombotic environment, as a result of enhanced activation of platelets and prothrombotic coagulation factors, coupled with impairment in the fibrinolytic system [3,4]. In particular, hypofibrinolysis is a key abnormality in diabetes Copyright: © 2021 by the authors. and appears to directly contribute to the enhanced vascular risk and the adverse outcome Licensee MDPI, Basel, Switzerland. in this population [5]. Notably, hypofibrinolysis can occur at an early age in diabetes [6] This article is an open access article and, therefore, this abnormality warrants closer scrutiny to understand the mechanistic distributed under the terms and pathways responsible and devise more effective treatment strategies. While a number of conditions of the Creative Commons pathways that control fibrinolysis are affected in diabetes, a central mechanism is related to Attribution (CC BY) license (https:// alteration in plasminogen activator inhibitor (PAI)-1 levels and/or function. The current creativecommons.org/licenses/by/ review summarises the role of PAI-1 in impaired fibrinolysis in diabetes and highlights 4.0/). Int. J. Mol. Sci. 2021, 22, 3170. https://doi.org/10.3390/ijms22063170 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 16 Int. J. Mol. Sci. 2021, 22, 3170 2 of 15 and highlights strategies to modulate PAI-1 levels or activity as a mean to improve the fibrinolytic process and reduce thrombosis risk. strategies to modulate PAI-1 levels or activity as a mean to improve the fibrinolytic process 1.1.and Fibrinolysis reduce thrombosis in Diabetes risk. The fibrinolytic process starts with the conversion of plasminogen into plasmin after 1.1. Fibrinolysis in Diabetes activation by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen ac- tivatorThe (u-PA). fibrinolytic Plasmin process is the starts main with protein the conversionthat cleaves of the plasminogen fibrin fibres into resulting plasmin in after the formationactivation of by fibrin tissue-type degradation plasminogen products activator [7]. Plasmin (t-PA) generation or urokinase-type is tightly controlled plasminogen not onlyactivator by activators (u-PA). Plasmin but also isinhibitors the main to protein avoid excessive that cleaves clot the lysis. fibrin PAI-1 fibres is one resulting of the inmost the formation of fibrin degradation products [7]. Plasmin generation is tightly controlled not powerful antifibrinolytic proteins that binds to t-PA or u-PA, inhibiting their function and only by activators but also inhibitors to avoid excessive clot lysis. PAI-1 is one of the most reducing plasmin generation [7]. powerful antifibrinolytic proteins that binds to t-PA or u-PA, inhibiting their function and Importantly, in patients with metabolic syndrome and/or type 2 diabetes, plasma reducing plasmin generation [7]. concentrations of PAI-1 are elevated, thus contributing to the hypofibrinolytic environ- Importantly, in patients with metabolic syndrome and/or type 2 diabetes, plasma ment [8,9]. In addition to the effect on clot lysis, recent evidence suggests that increased concentrations of PAI-1 are elevated, thus contributing to the hypofibrinolytic environ- vascular PAI-1 can directly accelerate the atherothrombotic process by promoting neoin- ment [8,9]. In addition to the effect on clot lysis, recent evidence suggests that increased timal plaque formation [10]. This indicates that abnormalities in the coagulation system vascular PAI-1 can directly accelerate the atherothrombotic process by promoting neointimal do not only affect thrombosis potential but can also contribute to the progression of ath- plaque formation [10]. This indicates that abnormalities in the coagulation system do not erosclerosis. only affect thrombosis potential but can also contribute to the progression of atherosclerosis. 1.2.1.2. PAI-1 PAI-1 Structure Structure and Function 1.2.1.1.2.1. PAI-1 PAI-1 Structure Structure PAI-1,PAI-1, a member of the superfamilysuperfamily ofof serineserine proteaseprotease inhibitors inhibitors (SERPIN) (SERPIN) [11 [11,12],,12], is is a asingle-chain single-chain glycoprotein glycoprotein of of approximately approximately 5252 kDakDa consistingconsisting ofof 379 or 381 amino acids dependingdepending on on heterogeneity heterogeneity of of the the N-terminal N-terminal caused caused by by two two potential potential cleavage cleavage sites sites for for signalsignal peptidase peptidase [13]. [13]. PAI-1 PAI-1 contains contains two two distinct distinct interactive interactive domains; domains; a a reactive reactive centre looploop (RCL) (RCL) and and a a flexible flexible joint joint region region with with helix helix D D (hD), (hD), helix helix E E (hE), (hE), and and helix helix F F (hF) (hF) bindingbinding sites as detaileddetailed inin FigureFigure1 [1 14[14].]. The The RCL RCL domain domain is is the the primary primary site site for for u-PA/t-PA u-PA/t- PAbinding binding and and contains contains a P1-P1’ a P1-P1’ peptide peptide bond bond that interactsthat interacts with thesewith these proteases proteases [15].PAI-1 [15]. PAI-1lacks cysteinelacks cysteine residues residues and hence and therehence is there an absence is an absence of disulfide of disulfide bonds that bonds can that account can accountfor its instability for its instability in solution. in Itsolution. includes It several includes residues several of residues methionine, of methionine, which may explainwhich mayits susceptibility explain its susceptibility to irreversible to inactivationirreversible byinactivation oxidising by agents. oxidising agents. Figure 1. SchematicSchematic depiction of thethe PAI-1PAI-1 conformationconformation as as well well as as its its interaction interaction with with vitronectin vitronectin cofactor cofactor and and plasminogen plasmino- genactivators activators (PA). (PA). PAI-1 PAI-1 contains contai twons distincttwo distinct interactive interactive domains: domains: a reactive a reactive centre centre loop loop (RCL) (RCL) and aand flexible a flexible joint joint region region with withhelix helix D (hD), D (hD), helix helix E (hE), E and(hE), helix and Fhelix (hF) F binding (hF) binding sites. Thesites. P1-P1’ The P1-P1’ bond isbond broken is broken to create to ancreate acyl–enzyme an acyl–enzyme intermediate inter- mediate following the creation of a non-covalent PAI-1/PA Michaelis complex. The reaction takes place through a
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