Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia

B. Nagy, J. Jin, B. Ashby, M. P. Reilly, S. P. Kunapuli

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background:In hypercholesterolemia, platelets demonstrate increased reactivity and promote the development of cardiovascular disease. Objective:This study was carried out to investigate the contribution of the ADP receptor P2Y12-mediated pathway to platelet hyperreactivity due to hypercholesterolemia. Methods:Low-density lipoprotein receptor-deficient mice and C57Bl/6 wild-type mice were fed on normal chow and high-fat (Western or Paigen) diets for 8weeks to generate differently elevated cholesterol levels. P2Y12 receptor-induced functional responses via Gi signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin. Platelet aggregation and secretion, αIIbβ3 receptor activation and the phosphorylation of extracellular signal-regulated protein kinase (ERK) and Akt were analyzed. Results:Plasma cholesterol levels ranged from 69±10 to 1011±185mgdL-1 depending on diet in mice with different genotypes. Agonist-dependent aggregation, dense and α-granule secretion and JON/A binding were gradually and significantly (Pi-mediated ERK and Akt phosphorylation in hypercholesterolemic mice vs. normocholesterolemic animals. In addition, blocking of the P2Y12 receptor by AR-C69931MX (Cangrelor) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls. Conclusions:These data revealed that the P2Y12 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia.

Original languageEnglish
Pages (from-to)810-819
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume9
Issue number4
DOIs
Publication statusPublished - Apr 2011

Fingerprint

Hypercholesterolemia
Blood Platelets
Platelet Aggregation
Phosphorylation
Diet
Purinergic P2 Receptors
LDL Receptors
Extracellular Signal-Regulated MAP Kinases
Indomethacin
Protein Kinases
Cardiovascular Diseases
Fats
Cholesterol
Genotype
cangrelor

Keywords

  • Hypercholesterolemia
  • Low-density lipoprotein receptor
  • P2Y12 receptor
  • Platelet signaling

ASJC Scopus subject areas

  • Hematology

Cite this

Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. / Nagy, B.; Jin, J.; Ashby, B.; Reilly, M. P.; Kunapuli, S. P.

In: Journal of Thrombosis and Haemostasis, Vol. 9, No. 4, 04.2011, p. 810-819.

Research output: Contribution to journalArticle

Nagy, B. ; Jin, J. ; Ashby, B. ; Reilly, M. P. ; Kunapuli, S. P. / Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. In: Journal of Thrombosis and Haemostasis. 2011 ; Vol. 9, No. 4. pp. 810-819.
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