Impaired myocardial t‐PA release in patients with coronary artery disease

Österlund, Barbro; Jern, Sverker; Jern, Christina; Seeman-Lodding, H.; Östman, Margareta; Johansson, Gillis; Biber, Björn

doi:10.1111/j.1399-6576.2008.01741.x

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…The fibrinolytic response has been shown to be deficient in large patient groups with cardiovascular risk factors such as hypertension, coronary disease, active smokers, renal failure as well as obesity [ 11 – 13 ]. Currently, the only way of regulating the plasma-levels of t-PA is by systemic administration of recombinant protein, an established treatment alternative in acute myocardial infarction, stroke and pulmonary embolism.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

et al. 2015

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The expression of the tissue plasminogen activator (t-PA) gene appears to be under epigenetic control and can be affected by histone deacetylation inhibition. The study aimed to test if histone deacetalyase inhibitor treatment lead to increased t-PA release or reduced exhaustion in t-PA release in response to stimulation, as well as change in plasminogen activator inhibitor-1 (PAI-1) in subjects with coronary disease. In this clinical study, 16 post-myocardial infarction subjects, the perfused forearm model was used with isoprenaline provocation during 20 minutes, to stimulate local t-PA release. Each subject was measured twice on the same day (repeated stimuli sequences) as well as on two different occasions, without treatment and after four weeks of treatment with valproic acid (500 mg, twice daily). Net forearm release for t-PA in response to isoprenaline at minutes 1.5, 3, 6, 9, 12, 15 and 18 was measured, allowing assessment of cumulative t-PA release. There was a reduction in the exhaustion of cumulative t-PA release during repeated and prolonged stimulation with valproic acid treatment compared to non-treatment. Plasma PAI-1 antigen was decreased following treatment compared to non-treatment (18.4 ± 10.0 vs. 11.0 ± 7.1 nanograms/ml respectively, mean with 95% confidence interval). These findings demonstrate that histone deacetylation inhibition increases the capacity for endogenous t-PA release in subjects with vascular disease. Furthermore, the fibrinolytic balance is favored with suppressed PAI-1 levels. More studies are needed to establish the clinical relevance of these findings.Trial registrationEU Clinical Trials Register 2012-004950-27

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Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

et al. 2015

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“…This indicates that in case of an impaired endogenous fibrinolysis due to a reduced capacity for t-PA release, intravascular thrombus formation may propagate and lead to arterial occlusion and tissue infarction. In line with this hypothesis, t-PA release has been found to be defective in certain conditions associated with increased risk of thrombotic events, such as hypertension [3], [4], [5], obesity [6] and coronary atherosclerosis [7], [8].…”

Section: Introductionmentioning

confidence: 79%

Role of Histone Acetylation in the Stimulatory Effect of Valproic Acid on Vascular Endothelial Tissue-Type Plasminogen Activator Expression

et al. 2012

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AimsStimulated release of tissue-type plasminogen activator (t-PA) is pivotal for an intravascular fibrinolytic response and protects the circulation from occluding thrombosis. Hence, an impaired t-PA production is associated with increased risk for atherothrombotic events. A pharmacological means to stimulate the production of this enzyme may thus be desirable. We investigated if the anti-epileptic drug valproic acid (VPA) is capable of enhancing t-PA expression in vitro in vascular endothelial cells, and further examined if its histone deacetylase (HDAC)-inhibitory activity is of importance for regulating t-PA expression.Methods and ResultsHuman endothelial cells were exposed to valproic acid and t-PA mRNA and protein levels were quantified. Potential changes in histone acetylation status globally and at the t-PA promoter were examined by western blot and chromatin immunoprecipitation. Valproic acid dose-dependently stimulated t-PA mRNA and protein expression in endothelial cells reaching a 2–4-fold increase at clinically relevant concentrations and 10-fold increase at maximal concentrations. Transcription profiling analysis revealed that t-PA is selectively targeted by this agent. Augmented histone acetylation was detected at the t-PA transcription start site, and an attenuated VPA-response was observed with siRNA knock of HDAC3, HDAC5 and HDAC7.ConclusionsValproic acid induces t-PA expression in cultured endothelial cells, and this is associated with increased histone acetylation at the t-PA promoter. Given the apparent potency of valproic acid in stimulating t-PA expression in vitro this substance may be a candidate for pharmacological modulation of endogenous fibrinolysis in man.

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“…It has been suggested that impaired fibrinolysis at the time of coronary angioplasty contributes to restenosis (15). Deficient local endothelial tissue-type plasminogen activator (TPA) release in patients with CAD indicates reduced local fibrinolytic capacity and might explain the increased risk of coronary thrombosis in this patient group (16). Recently, low plasma fibrinolytic potential, found in 10% of the population, was found to increase the relative risk of arterial thrombosis 2-fold (17).…”

Section: Significance Of Endogenous Fibrinolysis In Acute Coronary Symentioning

confidence: 98%

Prognostic Value of Plasma Fibrinolysis Activation Markers in Cardiovascular Disease

Gorog

2010

Journal of the American College of Cardiology

109

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The pivotal role of hypoactive endogenous fibrinolysis in the occurrence of thrombotic cardiovascular events is now well-recognized. To evaluate the diagnostic and prognostic role of impaired fibrinolysis, plasma fibrinolysis markers have been investigated in large prospective studies in both healthy individuals and patients with established coronary disease. Antigen and activity levels of components of the fibrinolytic system were measured by immunoassays, which replaced earlier global fibrinolysis tests. This review covers 45 studies in nearly 50,000 subjects, examining the association between plasma markers of fibrinolysis and coronary artery disease, to establish the usefulness of these markers in predicting future cardiovascular events. The predictive value of plasma levels of tissue-type plasminogen activator, platelet activator inhibitor-1, plasmin-antiplasmin complex, D-dimer, thrombin activatable fibrinolysis inhibitor, and lipoprotein(a) for major adverse cardiac events is highly variable and conflicting, especially after adjusting for conventional risk factors, judging from the published data in the last decade. The value of fibrinolysis activity markers is very limited in aiding diagnosis and risk stratification in the individual patient, on the basis of the weak prognostic values obtained in some studies and the lack of power in others. The physiological limitations of such markers in reflecting endogenous fibrinolysis is discussed. The emerging novel global assays of fibrinolysis will require large-scale clinical trials before their prognostic power or superiority to multiple biomarker measurements can be evaluated.

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Impaired myocardial t‐PA release in patients with coronary artery disease

Cited by 11 publications

References 38 publications

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

Role of Histone Acetylation in the Stimulatory Effect of Valproic Acid on Vascular Endothelial Tissue-Type Plasminogen Activator Expression

Prognostic Value of Plasma Fibrinolysis Activation Markers in Cardiovascular Disease

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