Background: The use of abacavir has been associated with cardiovascular disease. In earlier studies, we have demonstrated that abacavir induces an increase in endothelial ICAM-1 expression and promotes leukocyte recruitment through Mac-1/ICAM-1 interaction. Given the chemical structure of abacavir, we have previously explored the link between abacavir and its proinflammatory effects by interfering in the purine signalling pathway, and have seen that ATP and its P2X7 receptors are involved in the leukocyte accumulation induced by abacavir. The aim of the present study was to evaluate the role of ATP and its receptors in the endothelial ICAM-1 overexpression induced by abacavir.
Methods: Human umbilical vein or arterial endothelial cells (HUVEC or HUAEC, respectively) were pre-treated with antagonists of P2X7 ATP receptors [oxATP (600 µmol/L, 30 min) or A804598 (1 µmol/L, 30 min)] prior to administration of abacavir (10 µmol/L, 24h). Subsequently, ICAM-1 expression was measured by flow cytometry. Data represent the percentage of median fluorescence intensity vs. control group (100%) and are expressed as media±SEM. Statistical analysis was performed with one-way ANOVA and a Newman-Keuls post-hoc test, with significance *p<0.05 (vs. control) and +p<0.05 (vs. abacavir), n≥4.
Results: Clinical concentrations of abacavir (10 µmol/L, 24h) produced an increase in ICAM-1 expression on HUVEC (abacavir 10 µmol/L: 189.8±18.3** vs. 100% control) and HUAEC (abacavir 10 µmol/L: 156.3±6.1** vs. 100% control). When cells were pre-treated with P2X7 receptor antagonists, this ICAM-1 overexpression was reverted on HUVEC [(oxATP 600 µmol/L: 121.9±20.8+ vs. 100% control) or (A804598 1 µmol/L: 122.7±10.4++ vs. 100% control)] or HUAEC [(oxATP 600 µmol/L: 104.1±7.2++ vs. 100% control) or (A804598 1 µmol/L: 113.8±3.9++ vs. 100% control)].
Conclusions: Our results suggest that the increased levels of ATP induced by abacavir and its interaction with its P2X7 receptors promote overexpression of ICAM-1 in the venular and arterial endothelium. This process may be responsible for the leukocyte recruitment observed in the vascular damage associated with atherosclerosis and myocardial infarction in HIV patients treated with abacavir.