Ticagrelor Improves Endothelial Function by Decreasing Circulating Epidermal Growth Factor (EGF)

Abstract

Ticagrelor is one of the most powerful P2Y12 inhibitor. We have recently reported that, in patients with concomitant Stable Coronary Artery Disease (SCAD) and Chronic Obstructive Pulmonary Disease (COPD) undergoing percutaneous coronary intervention (PCI), treatment with ticagrelor, as compared to clopidogrel, is associated with an improvement of the endothelial function (Clinical Trial NCT02519608). In the present study, we showed that, in the same population, after 1 month treatment with ticagrelor, but not with clopidogrel, there is a decrease of the circulating levels of epidermal growth factor (EGF) and that these changes in circulating levels of EGF correlate with on-treatment platelet reactivity. Furthermore, in human umbilical vein endothelial cells (HUVEC) incubated with sera of the patients treated with ticagrelor, but not with clopidogrel there is an increase of p-eNOS levels. Finally, analyzing the changes in EGF and p-eNOS levels after treatment, we observed an inverse correlation between p-eNOS and EGF changes only in the ticagrelor group. Causality between EGF and eNOS activation was assessed in vitro in HUVEC where we showed that EGF decreases eNOS activity in a dose dependent manner. Taken together our data indicate that ticagrelor improves endothelial function by lowering circulating EGF that results in the activation of eNOS in the vascular endothelium.

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease

“…In acute coronary syndrome (ACS) patients, treatment with ticagrelor resulted in a reduced number of cardiovascular events and in improved peripheral arterial function compared to clopidogrel [3][4][5], suggesting that ticagrelor, beside its antiplatelet activity, modulates biological processes involved in cardiovascular protection. In patients with stable CAD and concomitant chronic obstructive pulmonary disease (COPD), we have shown that ticagrelor, compared with clopidogrel, is superior in improving biological markers of endothelial function [2,6]. These benefits are consistent with observations in patients with stable CAD and concomitant diabetes in which treatment with ticagrelor led to higher improvement of endothelial dysfunction in comparison to ticagrelor [7].…”

“…High levels of EGF and its receptor EGFR have been detected in lung tissue specimens of COPD patients [86] and high airway immunoreactivity has been associated to mucin hypersecretion in COPD [87]. EGF is involved in endothelial dysfunction, neointimal hyperplasia, cardiac hypertrophy and remodeling [88] and, as shown by us, reduction in circulating levels of EGF could be involved in the ticagrelor-mediated improvement of endothelial function in stable CAD/COPD patients [2]. The cross-talk between EGF and Notch signaling is well characterized: EGF and Notch pathways can cooperate in either synergistic or antagonistic fashion in malignancies [89] and the EGF, via EGFR, acts as a negative regulator of HES1 expression in keratinocytes [90].…”

“…In another study by our group, this approach was used, in parallel with measurements of changes in brachial wall shear stress and flow mediated dilation, to assess ED in patients that underwent surgical or transcatheter aortic valve replacement [56]. Of relevance, in stable CAD/COPD patients, following ticagrelor treatment we also found decreased serum levels of epidermal growth factor (EGF), increased NO generation in HUVECs treated with patient's serum, measured by diaminofluorescein (DAF) assay, and attenuated reactive oxygen species (ROS) production in PBMC isolated from patients, assessed by flow cytometric analysis [2,6]. In order to determine whether the observed changes of SIRT1 and HES1 mRNA could be related to these markers of endothelial function, and whether the different effect of the drugs on SIRT1 and HES1 mRNA could be explained by differences in antiplatelet activity, we conducted association analyses between changes in SIRT1 and HES1 mRNA and changes in the levels of EGF, ROS, apoptosis, NO and platelets reactive units (PRU) after 1-month treatment (changes were defined as the ratio between values at T30 over values at T0).…”

“…Dual antiplatelet therapy (DAPT), consisting of the co-administration of aspirin and of a P2Y 12 inhibitor, is the gold standard treatment for chronic stable coronary artery disease (CAD) patients following percutaneous coronary intervention (PCI). Among antiplatelet drugs, ticagrelor, due to its higher efficiency in inhibiting the P2Y 12 receptor, is a more potent platelet inhibitor as compared with clopidogrel [1,2]. In acute coronary syndrome (ACS) patients, treatment with ticagrelor resulted in a reduced number of cardiovascular events and in improved peripheral arterial function compared to clopidogrel [3][4][5], suggesting that ticagrelor, beside its antiplatelet activity, modulates biological processes involved in cardiovascular protection.…”

Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3)

“…Bioavailability of endothelial NO synthase (eNOS) generated NO is decreased in SCD by extracellular hemoglobin which scavenges NO [32,33]. Ticagrelor had positive effects on eNOS activity in endothelial cells [34][35][36]. Adenosine A 2A receptor agonists decreased hypoxia/ reoxygenation-induced tissue inflammation in a mouse model and in patients with SCD [37,38].…”