ApoE genotype affects biomarkers of chronic inflammation and oxidative stress as well as tissue vitamin E uptake

In Western societies the apoE4 genotype is associated with increased morbidity and mortality and represents a significant risk factor for cardiovascular disease. An increasing number of studies, as conducted in cultured cells, transgenic mice and human volunteers, are indicating higher oxidative stress and a more proinflammatory state associated with the apoE4 allele. ApoE4 macrophages exhibited increased membrane oxidation and produced more nitric oxide and superoxide anion free radicals than apoE3 cells. Furthermore in apoE4 macrophages an enhanced transactivation of the key redox sensitive transcription factor NF-kappaB accompanied by a higher production of proinflammatory cytokines (TNF-alpha, IL1-beta, IL6, MIP1-alpha), as compared to apoE3 cells, was evident. In a recent study we observed significant lower alpha-tocopherol (aToc) concentrations in the lung of apoE4 compared to apoE3 transgenic mice. Importantly, receptors of aToc uptake including scavenger receptor B1 (SR-B1), LDL receptor (LDLrec) and LDL receptor related protein 1 (LRP1) were lower in apoE4 compared to apoE3 mice. Lung mRNA levels of the ATP-binding cassette A1 (ABCA1) and the multidrug resistance transporter 1 (MDR1), surfactant proteins mediating the export of aToc, were lower in apoE4 than in apoE3 mice. In addition, the mRNA levels of cytochrome P4503A (CYP3A), an enzyme family involved in the degradation of aToc, tended to be higher in the apoE4 as compared to the apoE3 genotype. Thus, genes encoding for proteins involved in peripheral aToc transport and degradation are affected by the apoE genotype probably accounting for the lower aToc tissue concentration as observed in apoE4 mice.