Ticagrelor, a P2Y12 antagonist, attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein-E-deficient mice

Atherosclerosis. 2018 Aug:275:124-132. doi: 10.1016/j.atherosclerosis.2018.05.053. Epub 2018 May 31.

Abstract

Background and aims: Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe-/-) mice.

Methods: Eight-week-old male apoe-/- mice were fed a western-type diet (WTD) supplemented with 0.1% ticagrelor (approximately 120 mg/kg/day). Non-treated animals on WTD served as control. Atherosclerotic lesions were examined by en-face Sudan IV staining, histological analyses, quantitative RT-PCR analysis, and western blotting. Endothelial function was analyzed by acetylcholine-dependent vasodilation using aortic rings. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments.

Results: Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05).

Conclusions: Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS.

Keywords: Atherosclerosis; Endothelial function; Inflammation; P2Y12; Ticagrelor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects*
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Aorta, Thoracic / physiopathology
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / physiopathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Atherosclerosis / prevention & control*
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Phosphorylation
  • Plaque, Atherosclerotic*
  • Purinergic P2Y Receptor Antagonists / pharmacology*
  • Receptors, Purinergic P2Y12 / drug effects*
  • Receptors, Purinergic P2Y12 / metabolism
  • Ticagrelor / pharmacology*
  • Vasodilation / drug effects*

Substances

  • Inflammation Mediators
  • P2ry12 protein, mouse
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12
  • JNK Mitogen-Activated Protein Kinases
  • Ticagrelor