The Biochemistry, Physiology and Pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo

Craen, Britt Van De; Declerck, Paul; Gils, Ann

doi:10.1016/j.thromres.2012.06.023

Cited by 114 publications

(115 citation statements)

References 157 publications

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“…Thus, these simulations also help elucidate why some inhibitory serpin families are more conformationally labile than others. T he serpin plasminogen activator inhibitor 1 (PAI-1) negatively regulates blood clot clearance (fibrinolysis) by mechanically inhibiting important serine proteases, including tissue type plasminogen activator and urokinase type plasminogen activator (1). Suicide inhibition, initiated by proteolytic cleavage of the PAI-1 reactive center loop (RCL), requires insertion of the cleaved RCL into the central β-sheet (sheet A).…”

mentioning

confidence: 99%

“…Physiologically, this regulation is achieved by binding to the cell adhesion factor vitronectin, leading to an ∼50% increase in the active state t 1/2 (3). Because high levels of active PAI-1 are associated both with poor prognoses for some cancers, presumably due to interactions with vitronectin, and with cardiovascular diseases (1), PAI-1 inhibitors that accelerate the latency transition are under development (1,4,5). However, drug design efforts are hampered by the lack of detailed molecular mechanisms for PAI-1 conformational changes.…”

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confidence: 99%

“…1 To whom correspondence may be addressed. Email: pwintrod@rx.umaryland.edu, or faccioli@science.unitn.it.…”

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Serpin latency transition at atomic resolution

Cazzolli

Wang

Beccara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Protease inhibition by serpins requires a large conformational transition from an active, metastable state to an inactive, stable state. Similar reactions can also occur in the absence of proteases, and these latency transitions take hours, making their time scales many orders of magnitude larger than are currently accessible using conventional molecular dynamics simulations. Using a variational path sampling algorithm, we simulated the entire serpin active-to-latent transition in all-atom detail with a physically realistic force field using a standard computing cluster. These simulations provide a unifying picture explaining existing experimental data for the latency transition of the serpin plasminogen activator inhibitor-1 (PAI-1). They predict a long-lived intermediate that resembles a previously proposed, partially loop-inserted, prelatent state; correctly predict the effects of PAI-1 mutations on the kinetics; and provide a potential means to identify ligands able to accelerate the latency transition. Interestingly, although all of the simulated PAI-1 variants readily access the prelatent intermediate, this conformation is not populated in the active-to-latent transition of another serpin, α 1 -antitrypsin, which does not readily go latent. Thus, these simulations also help elucidate why some inhibitory serpin families are more conformationally labile than others. T he serpin plasminogen activator inhibitor 1 (PAI-1) negatively regulates blood clot clearance (fibrinolysis) by mechanically inhibiting important serine proteases, including tissue type plasminogen activator and urokinase type plasminogen activator (1). Suicide inhibition, initiated by proteolytic cleavage of the PAI-1 reactive center loop (RCL), requires insertion of the cleaved RCL into the central β-sheet (sheet A). This process expands sheet A, inhibits the covalently attached protease by mechanical disruption of the active site (2), and results in a thermodynamically stable serpin conformation. Alternatively, PAI-1 can spontaneously deactivate by inserting its intact, uncleaved RCL into sheet A, resulting in the more stable but inactive latent conformation (1) (Fig. 1).The latency transition provides a facile way to regulate PAI-1 activity. Physiologically, this regulation is achieved by binding to the cell adhesion factor vitronectin, leading to an ∼50% increase in the active state t 1/2 (3). Because high levels of active PAI-1 are associated both with poor prognoses for some cancers, presumably due to interactions with vitronectin, and with cardiovascular diseases (1), PAI-1 inhibitors that accelerate the latency transition are under development (1, 4, 5). However, drug design efforts are hampered by the lack of detailed molecular mechanisms for PAI-1 conformational changes. Numerous studies have identified mutations that either accelerate or retard the conformational transition, as well as antibodies that can accelerate latency. Despite these efforts, the molecular details of the latency transition and the residues involved in the key i...

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Serpin latency transition at atomic resolution

Cazzolli

Wang

Beccara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Plasmin formation is catalyzed by tissue-type (t-PA) or urokinase-type (u-PA) plasminogen activators. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of t-PA and u-PA, and it plays an important role in the removal of thrombi from the vascular system under thrombotic conditions [1]. Increased plasma PAI-1 levels suppress the normal fibrinolytic system and lead to prothrombotic states.…”

Section: Introductionmentioning

confidence: 99%

“…Increased plasma PAI-1 levels suppress the normal fibrinolytic system and lead to prothrombotic states. Thus, increased levels of plasma PAI-1 comprise a risk factor; serve as a marker for thrombotic diseases and onset of these diseases [1]. Levels of PAI-1 are elevated in various prothrombotic states such as hypertension, obesity, insulin resistance, diabetes and aging [2] [3] [4] [5].…”

Section: Introductionmentioning

confidence: 99%

Effects of Fermented Rice Vinegar Kurozu and Its Sediment on Inflammation-Induced Plasminogen Activator Inhibitor 1 (PAI-1) Increase

Ohkura¹,

Kihara-Negishi²,

Fujii³

et al. 2018

FNS

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Kurozu is a traditional black rice vinegar in Japan. Kurozu-moromi is the solid sediment that arises during the production of Kurozu. Kurozu is thought to have blood thinning and antithrombotic activities but a specific effect has not been proven. Plasma plasminogen activator inhibitor 1 (PAI-1) inhibits fibrinolysis and when elevated, it is a risk factor for the development of thrombotic diseases. Here, we examined the effects of a diet containing Kurozu and Kurozu-moromi on LPS (lipopolysaccharide)-induced increases in plasma PAI-1 levels in mice and on TNF-α (tumor necrosis factor α) increased PAI-1 production in the medium of a cultured endothelial cell line. Mice were fed with a diet containing 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu-moromi for four weeks, and then subcutaneously injected with 0.015 mg/kg of LPS in saline and sacrificed three hours later. Orally administered concentrated Kurozu and Kurozu-moromi significantly suppressed the LPS-induced increase in PAI-1 antigen and its activity in mouse plasma. The ethanol extract of Kurozu-moromi inhibited TNF-α induced increases of PAI-1 in the culture medium of the EA.hy926 endothelial cell line. The present findings showed that Kurozu and Kurozu-moromi contain natural products that decrease thrombotic tendencies by decreasing PAI-1 production in inflammatory states and have potential as antithrombotic foodstuffs.

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Matricellular proteins: Potential biomarkers in head and neck cancer

Wang,

Liu,

Wang

et al. 2024

Journal of Cell Communication and Signaling

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The extracellular matrix (ECM) is a complex network of diverse multidomain macromolecules, including collagen, proteoglycans, and fibronectin, that significantly contribute to the mechanical properties of tissues. Matricellular proteins (MCPs), as a family of non‐structural proteins, play a crucial role in regulating various ECM functions. They exert their biological effects by interacting with matrix proteins, cell surface receptors, cytokines, and proteases. These interactions govern essential cellular processes such as differentiation, proliferation, adhesion, migration as well as multiple signal transduction pathways. Consequently, MCPs are pivotal in maintaining tissue homeostasis while orchestrating intricate molecular mechanisms within the ECM framework. The expression level of MCPs in adult steady‐state tissues is significantly low; however, under pathological conditions such as inflammation and cancer, there is a substantial increase in their expression. In recent years, an increasing number of studies have focused on elucidating the role and significance of MCPs in the development and progression of head and neck cancer (HNC). During HNC progression, there is a remarkable upregulation in MCP expression. Through their distinctive structure and function, they actively promote tumor growth, invasion, epithelial‐mesenchymal transition, and lymphatic metastasis of HNC cells. Moreover, by binding to integrins and modulating various signaling pathways, they effectively execute their biological functions. Furthermore, MCPs also hold potential as prognostic indicators. Although the star proteins of various MCPs have been extensively investigated, there remains a plethora of MCP family members that necessitate further scrutiny. This article comprehensively examines the functionalities of each MCP and highlights the research advancements in the context of HNC, with an aim to identify novel biomarkers for HNC and propose promising avenues for future investigations.

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The Biochemistry, Physiology and Pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo

Cited by 114 publications

References 157 publications

Serpin latency transition at atomic resolution

Serpin latency transition at atomic resolution

Effects of Fermented Rice Vinegar Kurozu and Its Sediment on Inflammation-Induced Plasminogen Activator Inhibitor 1 (PAI-1) Increase

Matricellular proteins: Potential biomarkers in head and neck cancer

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