Background:
Sirolimus (sir) alone or in combination with cyclosporine (csa) or tacrolimus (tac) are used in solid organ transplantation, but uncertainty remains regarding their respective atherogenic potentials.
Methods:
Thp-1 cells were cultured as macrophages and then treated with plasma trough and peak concentration doses of sir, sir/csa or sir/tac to assess the time- and dose-dependent mrna or protein expression of selected atherogenic genes. the selected atherogenic genes included: the macrophage scavenger receptors (msrs) cd36, cd68, scavenger receptor (sr)-a, sr-bii, and lox-1; the nuclear hormone receptors peroxisome proliferator activated receptor gamma (ppargamma) and liver-x-receptor alpha (lxralpha); and the cholesterol efflux transporter (abca-1).
Results:
Sir-mediated changes in mrna included the upregulation of abca1, downregulation of cd68, sr-a and sr-bii, and concentration- and/or time-dependent effects on cd36, lox-1, ppargamma, and lxralpha that did not translate into significant protein changes. with sir/csa, the protein expressions of ppargamma and abca-1 were downregulated at 8 h. in contrast, with sir/tac, ppargamma, and abca-1 protein expressions were upregulated at 8 h.
Conclusions:
Combination results differed from findings with sir alone, supporting the observed clinical phenotype with calcineurin inhibitors. these findings may provide a rationale for the development of novel drug delivery strategies to mitigate adverse pharmacodynamic responses.