OBJECTIVE: The association of abacavir (ABC), a guanosine analogue, with cardiovascular toxicity is a long-lasting matter of controversy engendered by the lack of a mechanism of action. Clinical data point to an acute mechanism of vascular inflammation. Previous studies have shown that ABC induces leukocyte-endothelial cell interactions, an indicator of vascular inflammation. These effects are reproduced by another purine analogue, didanosine, but not by pyrimidine or acyclic nucleotide analogues, hinting at an interference with the purinergic system. The aim of the present study was to assess the role of ATP-receptors in leukocyte accumulation induced by ABC. DESIGN AND METHODS: Clinical concentrations of ABC were analysed in an animal model in vivo (intravital microscopy using male C57BL/6 wild-type or P2rx7 knockout mice), in human endothelial cells and leukocytes in vitro (flow chamber), or in leukocyte Mac-1 expression (flow cytometry). RESULTS: ABC reduced leukocyte rolling velocity and increased rolling flux and adhesion both in vivo and in vitro. These effects were absent in P2rx7 knockout mice and following the specific blockade of ATP-P2X7 receptors in wild-type animals. Further pharmacological characterization in flow chamber experiments confirmed the role of ATP-P2X7 receptors and suggested that those located on leukocytes were particularly implicated. Activation of ATP-P2X7 receptors is needed for expression of leukocytic Mac-1. Similar effects were obtained with didanosine. CONCLUSION: ABC induces leukocyte-endothelial cell interactions through a mechanism involving interference with purine-signalling pathways via ATP-P2X7 receptors located mainly on leukocytes. Our data are compatible with existing clinical data revealing an increased cardiovascular risk in ABC-treated patients.
OBJECTIVE: The association of abacavir (ABC), a guanosine analogue, with cardiovascular toxicity is a long-lasting matter of controversy engendered by the lack of a mechanism of action. Clinical data point to an acute mechanism of vascular inflammation. Previous studies have shown that ABC induces leukocyte-endothelial cell interactions, an indicator of vascular inflammation. These effects are reproduced by another purine analogue, didanosine, but not by pyrimidine or acyclic nucleotide analogues, hinting at an interference with the purinergic system. The aim of the present study was to assess the role of ATP-receptors in leukocyte accumulation induced by ABC. DESIGN AND METHODS: Clinical concentrations of ABC were analysed in an animal model in vivo (intravital microscopy using male C57BL/6 wild-type or P2rx7 knockout mice), in human endothelial cells and leukocytes in vitro (flow chamber), or in leukocyte Mac-1 expression (flow cytometry). RESULTS: ABC reduced leukocyte rolling velocity and increased rolling flux and adhesion both in vivo and in vitro. These effects were absent in P2rx7 knockout mice and following the specific blockade of ATP-P2X7 receptors in wild-type animals. Further pharmacological characterization in flow chamber experiments confirmed the role of ATP-P2X7 receptors and suggested that those located on leukocytes were particularly implicated. Activation of ATP-P2X7 receptors is needed for expression of leukocytic Mac-1. Similar effects were obtained with didanosine. CONCLUSION: ABC induces leukocyte-endothelial cell interactions through a mechanism involving interference with purine-signalling pathways via ATP-P2X7 receptors located mainly on leukocytes. Our data are compatible with existing clinical data revealing an increased cardiovascular risk in ABC-treated patients.
Authors: Víctor Collado-Díaz; Maria Ángeles Martinez-Cuesta; Maria Amparo Blanch-Ruiz; Ainhoa Sánchez-López; Patricia García-Martínez; José E Peris; Iris Usach; Maria Dolores Ivorra; Alessandra Lacetera; Sonsoles Martín-Santamaría; Juan V Esplugues; Angeles Alvarez Journal: Front Pharmacol Date: 2021-03-31 Impact factor: 5.810