Local Production of Soluble Urokinase Plasminogen Activator Receptor and Plasminogen Activator Inhibitor‐1 in the Coronary Circulation Is Associated With Coronary Endothelial Dysfunction in Humans

Corban, Michel; Prasad, Abhiram; Nesbitt, Lisa; Loeffler, Darrell; Herrmann, Joerg; Lerman, Lilach O.; Lerman, Amir

doi:10.1161/jaha.118.009881

Cited by 22 publications

(8 citation statements)

References 62 publications

(59 reference statements)

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“…PAI-1 is a major mediator in the function of endothelial fibrinolysis and macrophages-infiltration in cardiovascular diseases. The elevated PAI-1 initiates ECs dysfunction and enhances AS susceptibility [ 31 , 32 ]. Previous studies had demonstrated that HS could activate the expression of PAI-1 and adhesive molecules in endothelium [ 17 , 18 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

NFAT5 directs hyperosmotic stress-induced fibrin deposition and macrophage infiltration via PAI-1 in endothelium

Jiang

et al. 2020

Aging

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Although stress can significantly promote atherosclerosis, the underlying mechanisms are still not completely understood. Here we successfully unveiled that high salt-induced nuclear factor of activated T cells 5 (NFAT5) control the endothelial-dependent fibrinolytic activity and the inflammatory adhesion-related molecules expression through regulation of plasminogen activator inhibitor-1 (PAI-1). We first observed that high salt diets instigated the expression of NFAT5 and PAI-1 in the endothelium which brought about the fibrin deposition and macrophage infiltration in the atherosclerotic arteries of ApoE -/- mice. Overexpression of NFAT5 increased PAI-1-mediated antifibrinolytic activity and activated inflammatory adhesion-related genes in endothelial cells. Knockdown of NFAT5 by siRNA inhibited the expression of PAI-1, antifibrinolytic and adhesive molecules. Moreover, chromatin immunoprecipitation assay demonstrated that high salt intake significantly promoted the binding of NFAT5 to PAI-1 promoter (TGGAATTATTT) in endothelial cells. Our study identified that NFAT5 has great potential to activate the PAI-1-mediated fibrinolytic dysfunction and inflammatory cell adhesion, thus promoting high salt-induced atherosclerosis disease.

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Section: Discussionmentioning

confidence: 99%

NFAT5 directs hyperosmotic stress-induced fibrin deposition and macrophage infiltration via PAI-1 in endothelium

Jiang

et al. 2020

Aging

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“…[ 53 ] Recent studies have unveiled an association between suPAR and CMD in patients with non-obstructive CAD. [ 54 ] The net production of suPAR across the coronary circulation can be calculated as follows:…”

Section: Inflammatory Modulators Of Coronary Vascular Function: Beyond a Marker?mentioning

confidence: 99%

“…Positive values indicate the production or release of suPAR, whereas negative values indicate the retention or metabolism of suPAR in the coronary circulation. [ 54 ] Patients with endothelium-dependent CMD showed net transcoronary production of suPAR. [ 54 ]…”

Section: Inflammatory Modulators Of Coronary Vascular Function: Beyond a Marker?mentioning

confidence: 99%

Role of Inflammation in Coronary Epicardial and Microvascular Dysfunction

et al. 2021

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There is accumulating evidence highlighting a close relationship between inflammation and coronary microvascular dysfunction (CMD) in various experimental and clinical settings, with major clinical implications. Chronic low-grade vascular inflammation plays important roles in the underlying mechanisms behind CMD, especially in patients with coronary artery disease, obesity, heart failure with preserved ejection fraction and chronic inflammatory rheumatoid diseases. The central mechanisms of coronary vasomotion abnormalities comprise enhanced coronary vasoconstrictor reactivity, reduced endothelium-dependent and -independent coronary vasodilator capacity and increased coronary microvascular resistance, where inflammatory mediators and responses are substantially involved. How to modulate CMD to improve clinical outcomes of patients with the disorder and whether CMD management by targeting inflammatory responses can benefit patients remain challenging questions in need of further research. This review provides a concise overview of the current knowledge of the involvement of inflammation in the pathophysiology and molecular mechanisms of CMD from bench to bedside.

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“…Еще одним показателем, обнаружившим свое прогностическое значение в отношении ССО, оказался уровень ИАП-1 более 13,2 ед / мл. Данные небольших исследований, а также ряд мета-анализов сообщают о взаимосвязи повышения уровня ИАП-1 в плазме с «КС», смертью, сахарным диабетом, ИИ и удлинением времени лизиса эу-ОРИГИНАЛЬНЫЕ СТАТЬИ § глобулинового сгустка в плазме у пациентов с ФП [30][31][32][33][34]. Мы предполагаем, что обнаруженная нами прогностическая значимость ИАП-1 в отношении ССО отражает имеющееся у наших пациентов «бремя» атеротромбоза.…”

Section: оригинальные статьи §unclassified

Prediction-Determining Outcomes and Their Predictors in Atrial Fibrillation Patients Receiving Multicomponent Antithrombotic Therapy in Real Clinical Practice

et al. 2020

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Aim Searching for clinical, angiographic, and biochemical predictors of cardiovascular complications (CVC) and hemorrhagic complications in patients with atrial fibrillation (AF) receiving a multicomponent antithrombotic therapy (MAT) for an elective percutaneous coronary intervention (PCI). Patients with ischemic heart disease (IHD) and AF who require MAT for PCI are at a high risk of thrombotic complications (stroke, systemic embolism, coronary events) and hemorrhage. This warrants searching for new risk factors determining prediction of the outcome.Materials and methods This study included 207 patients (146 males aged 70.1±8.3 years) with IHD and AF who received direct oral anticoagulants (DOAC) as a part of their MAT therapy. Median duration of the follow-up was 12 [8.0; 12.0] months. The efficacy endpoint was a sum of CVCs combining cardiovascular death, ischemic stroke, venous thromboembolic complications, acute coronary syndrome (ACS), and requirement for an unscheduled PCI. “Coronary events”, including ACS and requirement for an unscheduled PCI were analyzed separately. The safety endpoint was BARC type 2-5 bleeding. Upon admission, biomarkers (growth-differentiation factor 15 (GDF-15), D-dimer, thrombin-activated fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-1 (PAI-1)) were measured for all patients. Searching for prognostically significant indexes was performed with the Cox proportional hazards regression.Results Incidence of all CVCs was 16.4 %. Independent predictors of CVC included the DOAC treatment at a reduced dose (odds ratio (OR) 2.5 at 95 % confidence interval (CI) 1.02-6.15; p=0.0454), GDF-15 >1191 pg /ml (OR 3.76 at 95 % CI, 1.26-11.18; p=0.0172), PAI-1 >13.2 U/ml (OR 2.67 at 95 % CI, 1.13-6,26; p=0.0245). Incidence of coronary complications was 9.2 %. Independent predictors of coronary complications included a SYNTAX index >26.5 (OR 4.5 at 95 % CI, 1.45-13.60; p=0.0090), PCI for chronic coronary occlusion (OR 3.21 at 95 % CI, 1.10-9.33; p=0.0326), a GDF-15 >1191 pg/ml (ОR 4.70 at 95 % CI, 1.32-16.81; p=0.0172). Incidence of BARC type 2-5 bleeding was 26.1 %. The only independent predictor for hemorrhage complications was the total PRECISE-DAPT score >30 (ОR 3.22; 95 % CI, 1.89-5.51; р<0.0001).Conclusion Three independent predictors of CVC were identified for patients with IHD and AF treated with MAT following an elective PCI: treatment with a reduced dose of DOAC, GDF-15 >1191 pg /ml, and PAI-1>13.2 U/ml. Independent predictors of coronary complications included a SYNTAX index >26.5, PCI for chronic coronary occlusion, and GDF-15 >1191 pg/ml. The factor associated with a risk of bleeding was the total PRECISE-DAPT score >30.

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Local Production of Soluble Urokinase Plasminogen Activator Receptor and Plasminogen Activator Inhibitor‐1 in the Coronary Circulation Is Associated With Coronary Endothelial Dysfunction in Humans

Cited by 22 publications

References 62 publications

NFAT5 directs hyperosmotic stress-induced fibrin deposition and macrophage infiltration via PAI-1 in endothelium

NFAT5 directs hyperosmotic stress-induced fibrin deposition and macrophage infiltration via PAI-1 in endothelium

Role of Inflammation in Coronary Epicardial and Microvascular Dysfunction

Prediction-Determining Outcomes and Their Predictors in Atrial Fibrillation Patients Receiving Multicomponent Antithrombotic Therapy in Real Clinical Practice

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