Last update 01 Nov 2024

Plasminogen activators x uPA

Last update 01 Nov 2024

Basic Info

Related Targets

Plasminogen activatorsuPA

Drugs associated with Plasminogen activators x uPA

CVS-3083

Target

Plasminogen activators x uPA

Mechanism

Plasminogen activators stimulants [+1]

Active Org.-

Originator Org.

Dendreon Pharmaceuticals, Inc.

Active Indication-

Inactive Indication

Diabetic Retinopathy [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Plasminogen activators x uPA

100 Translational Medicine associated with Plasminogen activators x uPA

0 Patents (Medical) associated with Plasminogen activators x uPA

424

Literatures (Medical) associated with Plasminogen activators x uPA

22 Sep 2023·bioRxiv : the preprint server for biology

PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.

Author: Teos, Leyla ; Kudryashova, Tatiana V ; Jiang, Lifeng ; Saiyed, Aisha ; Newcomb, Geoffrey ; Kelso, Michael J ; McGuckin, Joshua P ; DeLisser, Horace M ; Lin, Derek ; Buckley, Benjamin J ; Farkas, Laszlo ; Poncz, Mortimer ; Goncharov, Dmitry ; Stepanova, Victoria ; Ranson, Marie ; Cines, Douglas B ; Zaitsev, Sergei ; Goncharova, Elena A ; Bogamuwa, Srimathi ; Zhyvylo, Iryna ; Piper, Bryce ; Wolters, Paul J

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

01 Apr 2023·Cellular Signalling

Cardiomyocyte PAI-1 influences the cardiac transcriptome and limits the extent of cardiac fibrosis in response to left ventricular pressure overload

Article

Author: Eren, Mesut ; Shang, Meng ; Keating, Anna ; Lux, Elizabeth ; Vaughan, Douglas E ; Wilsbacher, Lisa D ; Kalousdian, Anthony A ; Ghosh, Asish K

Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid-acting inhibitor of endogenous plasminogen activators (uPA and tPA). The global PAI-1 knockout mice (PAI-1KO) develop age-dependent cardiac-selective fibrosis, and young global PAI-1KO mice exhibit augmented susceptibility to developing cardiac fibrosis in response to hypertension. Here, we tested the hypothesis that cardiomyocyte PAI-1 is necessary to provide cardioprotective effects in a left ventricular pressure overload-induced murine model of cardiac hypertrophy and fibrosis using cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) mice. The results revealed that cmPAI-1KO mice display significantly worse cardiac fibrosis than controls. To investigate the molecular mechanisms responsible for these effects, genome-wide cardiac transcriptome analysis was performed. Loss of cardiomyocyte PAI-1 led to differential expression of 978 genes compared to controls in response to left ventricular pressure overload. Pathway enrichment analysis identified the inflammatory response, cell substrate adhesion, regulation of cytokine production, leukocyte migration, extracellular matrix organization, and cytokine-mediated signaling pathways as being significantly upregulated in cmPAI-1KO hearts. Conversely, specific epigenetic repressors, cation transmembrane transport, muscle system processes, and nitric oxide signaling were significantly downregulated in cmPAI-1KO hearts compared to control hearts in response to left ventricular pressure overload. Collectively, the present study provides strong evidence of the impact of cardiomyocyte PAI-1 in regulation of the transcriptome network involved in the cardiac stress response. In response to stress, the deregulatory impact of cardiomyocyte PAI-1 loss on the cardiac transcriptome may be the underlying cause of cardiac-selective accelerated fibrogenesis in global PAI-1-deficient mice.

01 Mar 2022·Reproductive SciencesQ3 · MEDICINE

The Plasminogen Activator System, Glucocorticoid, and Mineralocorticoid Receptors in the Primate Endometrium During Artificial Menstrual Cycles

Q3 · MEDICINE

Article

Author: Slayden, Ov D ; Archer, David F ; Demirel, Esra ; Sabouni, Reem ; Chandra, Neelima

As a key mechanism in fibrinolysis and tissue remodeling, the plasminogen activator system has been suggested in the process of endometrial shedding and tissue remodeling. Previous studies have explored the role of estrogen, progesterone, and androgen receptors as well as elements of the renin-angiotensin-aldosterone system in shaping the morphology of the endometrium. This study investigates the distribution and concentrations of the mineralocorticoid receptor, glucocorticoid receptor, tissue plasminogen activator, urokinase plasminogen activator, and plasminogen activator inhibitor-1 within the endometrial stroma, glandular, and endothelial cells of the primate endometrium during artificial menstrual cycles. Our immunohistochemistry quantification shows mineralocorticoid and glucocorticoid receptors are ubiquitously distributed within the macaque endometrium with their patterns of expression following similar fluctuations to urokinase and tissue plasminogen activators particularly within the endometrial vasculature. These proteins are present in endometrial vasculature in high levels during the proliferative phase, decreasing levels during the secretory phase followed by rising levels in the menstrual phase. These similarities could suggest overlapping pathways and interactions between the plasminogen activator system and the steroid receptors within the endometrium. Given the anti-inflammatory properties of glucocorticoids and the role of plasminogen activators in endometrial breakdown, the glucocorticoid receptor may be contributing to stabilizing the endometrium by regulating plasminogen activators during the proliferative phase and menstruation. Furthermore, given the anti-mineralocorticoid properties of certain anti-androgenic progestins and their reduced unscheduled uterine bleeding patterns, the mineralocorticoid receptor may be involved in unscheduled endometrial bleeding.

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