Possible mechanisms underlying abacavir-related cardiovascular complications

Abstract

Abacavir is a nucleoside reverse transcriptase inhibitor commonly used for the treatment of HIV infection. However, several clinical studies indicated that patients receiving abacavir treatment were connected to an increase in cardiovascular risks. Since the underlying mechanism is still unclear, we would like to find out the reason of abacavir-induced cardiovascular risks. The effects of abacavir on vascular functions and platelet activities were observed. Sprague-Dawley rats (330-350 g) were fed with two doses of abacavir (16 mg/kg/day and 160 mg/kg/day) intragastrically for 28 days. Isometric tensions of basilar arteries were measured afterwards. Messenger RNA levels of eNOS, COX-2, MCP-1, I-CAM and V-CAM in aortae, mesenteric arteries and pulmonary arteries were measured by RT-PCR. For the determination of platelet activation, plasma level of CD40L, a platelet-derived factor, was measured by ELLSA kit. Moreover, the effect of abacavir on viability of human brain microvascular endothelial cells (HBMEC) was tested by MTT assay. Results from myograph studies showed that, after the treatment of abacavir, although the dose-response curve for acetylcholine-induced relaxation is slightly right-shifted, the maximum relaxation was not changed. Besides, there was no significant change in the mRNA levels of COX-2, MCP-1, I-CAM and V-CAM in rat aortae, mesenteric arteries and pulmonary arteries after the abacavir treatment. However, the mRNA level of eNOS was decreased in pulmonary arteries in abacavir-treated group. Also, a higher plasma level of CD40L was detected in the abacavir-treated group. The results of MTT assay showed that abacavir inhibited the growth of HBMEC. Abacavir did not affect the endothelium-dependent relaxation in basilar arteries nor change the mRNA level of eNOS in aortae and mesenteric arteries. However, mRNA level of eNOS was decreased in pulmonary arteries. It shows that the effect of abacavir on the vascular tone may be localized to certain vascular beds. The inhibition of endothelial cell growth suggested that abacavir may be toxic to endothelial cells. Abacavir may also increase the chance of developing thrombosis through the upregulation of the platelet activity. These findings may give hint to the possible mechanisms involved in the increase in cardiovascular risks by abacavir.