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Clinical Trial
. 2020 Feb 25;21(5):1576.
doi: 10.3390/ijms21051576.

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

Giorgio Aquila  1 , Francesco Vieceli Dalla Sega  2 , Luisa Marracino  3 , Rita Pavasini  4 , Laura Sofia Cardelli  4 , Anna Piredda  4 , Alessandra Scoccia  4 , Valeria Martino  1 , Francesca Fortini  2 , Ilaria Bononi  3 , Fernanda Martini  3 , Marco Manfrini  2 , Antonio Pannuti  5 , Roberto Ferrari  2   4 , Paola Rizzo  2   3 , Gianluca Campo  2   4
Affiliations
Clinical Trial

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

Giorgio Aquila et al. Int J Mol Sci. .

Abstract

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.

Keywords: Clopidogrel; Notch signaling; SIRT1; coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), Ticagrelor.

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Conflict of interest statement

Gianluca Campo has received honoraria for lectures from AstraZeneca, Menarini, Abbott Vascular, Boston Scientific. The other authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Droplet digital (dd) PCR based analysis of the expression of inflammation- and oxidative stress-related genes in peripheral blood cells of stable coronary artery disease (CAD)/concomitant chronic obstructive pulmonary disease (COPD) patients following 1-month treatment with ticagrelor and clopidogrel. Scatter plots, with medians, of the expression levels of RORγt (A), FoxP3 (B), NLRP3 (C), ICAM1 (D), and JAG1 (E) are shown. The absolute quantity of cDNA (copies/µL) was normalized to the average number of copies of GUSB. Follow up vs. baseline gene expression values, ANOVA test. Comparison of gene expression levels at baseline, student t test.
Figure 2
Figure 2
Droplet digital (dd) PCR based analysis of the levels of SIRT1 and HES1 mRNA in peripheral blood cells of stable CAD/COPD patients following 1-month treatment with ticagrelor or clopidogrel. Scatter plots, with medians, of the expression levels of SIRT1 (A) and HES1 (B) in peripheral blood cells of stable CAD/COPD patients following 1-month treatment with ticagrelor or clopidogrel. The absolute quantity of cDNA (copies/µL) was normalized to the average number of copies of GUSB. Follow up vs. baseline gene expression values, ANOVA test, * p < 0.05 and ** p < 0.01. Comparison of gene expression levels at baseline, student t test, ** p < 0.01.
Figure 3
Figure 3
Before-after analysis of SIRT1 and HES1. Before-after plot of SIRT1 (A) and HES1 (B) gene expression in peripheral blood cells from patients before and after one month of treatment with clopidogrel or ticagrelor. For clarity, only changes in gene expression higher than 20% of the values at baseline are connected and color-coded (red for fold changes >1.2 and blue for <0.8).
Figure 4
Figure 4
Correlation analyses. (A) Correlation between changes in SIRT1 and HES1 mRNA expression levels and changes in serum levels of Epidermal Growth Factor (EGF). Correlations were assessed by Spearman’s correlation test (HES1, R = −0.469, p < 0.01; SIRT1, R = −0.440, p < 0.01). (B) Correlation between changes in HES1 and SIRT1 mRNA expression levels. Correlations were assessed by Spearman’s correlation test (R = 0.466, p < 0.01). SIRT1 and HES1 changes were defined as ratio between mRNA levels after (T30) and before (T0) treatment with ticagrelor or clopidogrel. EGF changes were expressed as ratio between serum EGF concentration at T30 over serum EGF concentration at T0.
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