Acyl derivatives of coenzyme A inhibit platelet function via antagonism at P2Y₁ and P2Y₁₂ receptors: A new finding that may influence the design of anti-thrombotic agents

Abstract

We have performed a detailed investigation of the effects on platelet function of coenzyme A (CoA) and several acyl-CoAs. Platelet aggregation was measured by turbidimetry and by platelet counting; platelet shape change was measured using light scattering; P-selectin, Ca²⁺ mobilization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation were measured by flow cytometry. The compounds investigated inhibited ADP-induced platelet aggregation; those with saturated acyl groups containing 16-18 carbons were most effective. The effects of palmitoyl-CoA (16:0) were studied in depth. It inhibited platelet shape change and Ca²⁺ mobilization brought about by ADP (but not other agonists) indicating antagonism at P2Y₁ receptors, and also inhibited ADP-induced P-selectin expression. Effects of palmitoyl-CoA on the platelet aggregation and Ca²⁺ mobilization induced by several different agonists and agonist combinations were compared with those of MRS 2179 (a P2Y₁ antagonist) and AR-C69931 (a P2Y₁₂ antagonist), and were consistent with palmitoyl-CoA acting mainly at P2Y₁ but also with partial antagonism at P2Y₁₂ receptors. Antagonism at P2Y₁₂ receptors was confirmed in studies of VASP-phosphorylation. Palmitoyl-CoA did not act as an antagonist at P2X₁ receptors. The results are discussed in relation to the possibility that acyl-CoAs may contribute as endogenous modulators of platelet function and might serve as lead compounds for the design of novel antithrombotics.

• Coenzyme A
• acyl-coenzyme A
• palmitoyl-coenzyme A
• adenosine diphosphate
• P2Y₁ receptors
• P2Y₁₂ receptors
• ADP antagonists