Aspirin resistance in coronary artery disease is correlated to elevated markers for oxidative stress but not to the expression of cyclooxygenase (COX) 1/2, a novel COX-1 polymorphism or the PlA1/2polymorphism

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Abstract
Aspirin resistance (AR) is estimated to be present in 5–75% of patients and is related to increased cardiovascular mortality. However, the underlying mechanisms are mostly unknown. In the present study, AR was detected in 14 out of 55 patients (25%) with coronary artery disease. The presence of concomitant anti-inflammatory drugs did not affect AR. Plasma levels of thromboxane B2 as well as the markers for oxidative stress and known platelet activators 8-isoprostane and lipid peroxidation products were significantly higher in aspirin-resistant individuals (349.3 pg/ml, 53.9 pg/ml, and 538 µmol/l) compared to controls (113.7 pg/ml, 10.3 pg/ml, and 32.2 µmol/l; P < 0.05, respectively). Platelet cyclooxygenase-1 (COX-1) and COX-2 mRNA and protein expression were without significant differences between the two groups. DNA sequencing detected a novel platelet COX-1 single nucleotide polymorphism (SNP) resulting in amino acid exchange at position 8 (Arg8/Trp8). The wild-type as well as the heterozygous and homozygous SNP were present in both patient groups without significant differences. The aspirin binding (Arg120) and acetylation site (Ser529) were unaffected in the samples tested. Neither was AR related to the platelet integrin PlA1/A2 polymorphism. In conclusion, AR appears to be unrelated to differences in platelet COX-1 and COX-2 expression or to a novel platelet COX-1 SNP and the PlA1/A2 SNP. However, a correlation exists to elevated eicosanoids generated by oxidative stress indicating COX-1-independent pathways for the generation of platelet activating molecules represent a potential cause for AR.