CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine.

The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6+/-3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29-0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.

Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase.

Apolipoprotein (apo) E-deficient mice display marked accumulation in the plasma of VLDL deficient in both apoE and apoB100 but containing apoB48, apoA-I, apoCs, and apoA-IV. Since apoE-deficient mice develop severe atherosclerotic lesions with lipid-laden macrophages, we reasoned that the uptake of lipoproteins by intimal macrophages can take place in the absence of both apoE and apoB100. To get more insight into the mechanism of foam cell formation in apoE-deficient mice, we measured the interaction of VLDL from apoE-deficient mice (apoEnull VLDL) with the murine macrophage cell line J774. Scatchard analysis revealed that apoEnull VLDL is bound to J774 cells with a Kd value comparable to that of control VLDL (8.1 versus 4.7 micrograms/mL) and with a Bmax value about half that of control VLDL (40 versus 70 ng/mg cell protein, respectively). ApoEnull VLDL is also taken up and degraded by J774 macrophages via a high-affinity process less efficiently than control mouse VLDL (6-fold and 50-fold less efficiently, respectively). In line with this observation, incubation of J774 cells with 50 micrograms/mL apoEnull VLDL for 24 hours resulted in an increase in intracellular cholesteryl ester (CE) content, although 5-fold less pronounced than after incubation with 50 micrograms/mL control mouse VLDL. Under the conditions applied, simultaneous addition of 5 micrograms/mL lipoprotein lipase (LPL) stimulated the cellular uptake and degradation of apoEnull VLDL about 10-fold and resulted in a 5-fold stimulation of the intracellular CE accumulation, from 9 +/- 2 to 46 +/- 5 micrograms CE per milligram cell protein. In contrast to control mouse VLDL, apoEnull VLDL could not compete with 125I-labeled LDL for binding to the LDL receptor of J774 cells. Furthermore, neither LDL nor acetylated LDL could compete with 125I-labeled apoEnull VLDL for binding to these cells, whereas control mouse VLDL, VLDL from a hypertriglyceridemic patient, and apoEnull VLDL itself were efficient competitors. Thus, VLDL from apoE-deficient mice is taken up by J774 macrophages through recognition by a distinct receptor, which could be the triglyceride-rich lipoprotein receptor. We conclude that in apoE-deficient mice, foam cell formation occurs via a receptor-mediated uptake of apoEnull VLDL, which can be stimulated by the presence of LPL.