title: Abacavir induces platelet-endothelium interactions by interfering with purinergic signalling: A step from inflammation to thrombosis.
abstract: The controversy connecting Abacavir (ABC) with cardiovascular disease has been fuelled by the lack of a credible mechanism of action. ABC shares structural similarities with endogenous purines, signalling molecules capable of triggering prothrombotic/proinflammatory programmes. Platelets are leading actors in the process of thrombosis. Our study addresses the effects of ABC on interactions between platelets and other vascular cells, while exploring the adhesion molecules implicated and the potential interference with the purinergic signalling pathway. The effects of ABC on platelet aggregation and platelet-endothelium interactions were evaluated, respectively, with an aggregometer and a flow chamber system that reproduced conditions in vivo. The role of adhesion molecules and purinergic receptors in endothelial and platelet populations was assessed by selective pre-incubation with specific antagonists and antibodies. ABC and carbovir triphosphate (CBT) levels were evaluated by HPLC. The results showed that ABC promoted the adherence of platelets to endothelial cells, a crucial step for the formation of thrombi. This was not a consequence of a direct effect of ABC on platelets, but resulted from activation of the endothelium via purinergic ATP-P2X7receptors, which subsequently triggered an interplay between P-selectin and ICAM-1 on endothelial cells with constitutively expressed GPIIb/IIIa and GPIbα on platelets. ABC did not induce platelet activation (P-selectin expression or Ca2+mobilization) or aggregation, even at high concentrations. CBT levels in endothelial cells were lower than those required to induce platelet-endothelium interactions. Thus, ABC interference with endothelial purinergic signalling leads to platelet recruitment. This highlights the endothelium as the main cell target of ABC in this interaction, which is in line with previous experimental evidence that ABC induces manifestations of vascular inflammation.
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; Universidad Jaume I, Facultad de Ciencias de la Salud, Castellón de la Plana, Spain. Electronic address: angeles.alvarez@uv.es.
authors.forename: Angeles
authors.initials: A
authors.lastname: Alvarez
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO-Fundación Hospital Universitario Dr. Peset, Valencia, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: Rios-Navarro
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: Maria Amparo
authors.initials: MA
authors.lastname: Blanch-Ruiz
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Collado-Diaz
authors.affiliation: FISABIO-Fundación Hospital Universitario Dr. Peset, Valencia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Andujar
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Martinez-Cuesta
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO-Fundación Hospital Universitario Dr. Peset, Valencia, Spain.
authors.forename: Samuel
authors.initials: S
authors.lastname: Orden
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO-Fundación Hospital Universitario Dr. Peset, Valencia, Spain.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Esplugues
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002318:Cardiovascular Diseases / Q000209:etiology; D003848:Deoxyguanine Nucleotides / Q000032:analysis; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D019007:P-Selectin / Q000502:physiology; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D011687:Purines / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013927:Thrombosis / Q000209:etiology; D000099227:Abacavir; D006160:Guanosine Triphosphate
chemical_list: D019380:Anti-HIV Agents; D003848:Deoxyguanine Nucleotides; D015224:Dideoxynucleosides; D018799:Intercellular Adhesion Molecule-1; D019007:P-Selectin; D011687:Purines; D000099227:Abacavir; C573420:ICAM1 protein, human; C546937:SELP protein, human; C066928:carbovir triphosphate; D006160:Guanosine Triphosphate
keywords: Abacavir; Cardiovascular diseases; NRTIs; Platelet-endothelium interactions