Key result
Ticagrelor reduces endothelial cell apoptosis by ~2 percentage points compared to clopidogrel at one month.
Why the study?
The mechanisms underlying the superior improvement in endothelial function markers with ticagrelor compared with clopidogrel in patients with stable CAD and COPD undergoing PCI were unknown.
Does ticagrelor improve endothelial apoptosis and modulate SIRT1 and HES1 mRNA expression compared to clopidogrel in patients with stable CAD and COPD?
RCT (n=46)
Open-label
randomized
No
Does ticagrelor improve endothelial apoptosis and modulate SIRT1 and HES1 mRNA expression compared to clopidogrel in patients with stable CAD and COPD?
Ticagrelor reduces markers of endothelial dysfunction and upregulates SIRT1 and HES1 expression, suggesting pleiotropic anti-inflammatory properties beyond platelet inhibition.
Ticagrelor may confer endothelial protection in stable CAD with COPD; extends mechanistic evidence on pleiotropic effects beyond platelet inhibition.
Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.
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Aquila et al. (2020) conducted an RCT in Stable coronary artery disease with concomitant chronic obstructive pulmonary disease (n=46). Ticagrelor vs. Clopidogrel was evaluated on 1-month rate of human umbilical vein endothelial cells (HUVECs) apoptosis (p=<0.001). One-month treatment with ticagrelor significantly reduced the rate of HUVECs apoptosis (7.4% vs 9.3%, p<0.001) and increased SIRT1 and HES1 mRNA levels compared to clopidogrel.
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