Blood lipids, serum TSLP and weight levels in the five groups at the week 16.

<p>ND, HCD, T1, T2 and T3 groups were treated as described in the Methods section. TC: total cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol. TSLP: Thymic stromal lymphopoietin.</p><p>Blood lipids, serum TSLP and weight levels in the five groups at the week 16.</p

Plasma cytokines levels in each group.

<p>Note: The data are given as the mean±SD.</p>**<p>P<0.01 vs. CPS,</p>#<p>P<0.05 vs. SAP,</p>##<p>P<0.01 vs. SAP.</p

A Potential Mechanism of High-Dose Ticagrelor in Modulating Platelet Activity and Atherosclerosis Mediated by Thymic Stromal Lymphopoietin Receptor

<div><p>Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway.</p></div

Correlation coefficients and the scatterplots of TSLPR in transcription with each index of T3 group.

<p>(A) Correlation between TSLPR transcriptional level from platelet (mRNA expression) and Akt1 mRNA expression from platelet. (B) Correlation between TSLPR transcriptional level from platelet (mRNA expression) and aggregation. (C) Correlation between TSLPR transcriptional level from vascular histology (mRNA expression) and Akt1 mRNA expression of plaque lesion. (D) Correlation between TSLPR transcriptional level from vascular histology (mRNA expression) and palque area. (E) Correlation between TSLPR transcriptional level from vascular histology (mRNA expression) and vulnerability index. P<0.01 for all.</p

Photomicrographs of representative sections of ascending aorta from the five groups (immunohistochemistry, 200×).

<p>Vessel wall cells stained dark blue were considered positive for TSLPR expression. Cytoplasm and matrix stained yellow brown were considered positive for Akt1 expression. The mean density of TSLPR coincided well with that of Akt1 in plaques. HCD increased the expression of these markers, while only high-dose ticagrelor (100 mg/kg/d) and ND decreased their expression.</p

Spearman’s correlation between IL-35 and IL-27 concentrations and LVEF.

<p>A: IL-35 concentrations were positively correlated with LVEF in CAD (R = 0.416, P<0.01). B: IL-27 concentrations were negatively correlated with LVEF in CAD (R = −0.205, P<0.01).</p

After 16 weeks of high-cholesterol diet, TSLPR, CD62, and CD63 expression on platelet surface were not significantly different between the HCD, T1 (ticagrelor 25 mg/kg/d), and T2 (ticagrelor 50 mg/kg/d) groups.

<p>Ticagrelor at 100 mg/kg/d in the T3 group significantly decreased TSLPR, CD62, and CD63 expression on platelet surface. *P<0.01 vs. HCD. #P<0.01 vs. T1 and T2.</p

Gene expression of Akt1 and TSLPR (mRNA) in each group.

<p>Local vascular histology (top) and cytology platelet levels (bottom) showed higher levels of Akt1 and TSLPR in the HCD, T1, and T2 groups. The two indices were markedly decreased in the T3 group (100 mg/kg/d). There was no significant difference between the HCD, T1, and T2 groups. *P<0.01 vs. HCD. #P<0.01 vs. T1 and T2.</p

Representative western blots of TSLPR, Akt1, and GAPDH in all groups (A, B).

<p>Values are presented in the bottom histogram for the five groups (C, D). Vascular histology (A, C) and cytology platelet levels (B, D) showed higher levels of Akt1 and TSLPR in the HCD, T1, and T2 groups. *P<0.01 vs. HCD. #P<0.01 vs. T1 and T2.</p

Photomicrographs of representative sections of ascending aorta from the five groups (magnification 40×).

<p>After 16 weeks of high-cholesterol diet, larger corrected plaque area and vulnerability index were observed in the HCD, T1, and T2 groups compared with those in the T3 group. However, there was no significant difference of corrected plaque area and vulnerability index between the HCD, T1 and T2 groups. *P<0.01 vs. HCD. #P<0.01 vs. T1 and T2.</p