Roles of Apolipoprotein E (ApoE) and Inducible Nitric Oxide Synthase (iNOS) in Inflammation and Apoptosis in Preeclampsia Pathogenesis and Progression

OBJECTIVES: To investigate potential roles of inducible nitric oxide synthase (iNOS) and apolipoprotein (apoE) in inflammation and apoptosis promoting pathological changes in preeclampsia in pregnant mice with apoE and/or iNOS knock out. METHODS: B6.129 mice were crossed to produce WT, apoE(−/−), apoE(+/−), iNOS(−/−), iNOS(+/−) and apoE(−/−)iNOS(−/−) groups. Variants were confirmed by PCR. Serum lipid parameters (triglycerides, TG; total cholesterol, TC; high density lipoprotein, HDL; and low density lipoprotein, LDL), NO levels and placental electronic microscopic ultrastructures were evaluated, and blood pressure (BP), 24-hour urine protein and pregnancy outcomes were recorded for pregnant F1 generation mice. Placental expressions of inflammatory (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6; nuclear factor-κB, NF-κb) and apoptotic markers (Bcl-2 associated X protein, Bax, B-cell lymphoma/leukemia-2, Bcl-2, and Caspase-3) were evaluated via Western blot. RESULTS: Serum lipids, BP and 24-hour urine protein levels were shown to be significantly higher and parturition and placenta weights were lower in apoE(−/−) and apoE(−/−)iNOS(−/−) groups (p<0.05). NO levels were lower in the apoE(−/−)iNOS(−/−) group. In addition, inflammatory/apoptosis parameters, including TNF-α, IL-6, NF-κb, Bax, Bcl-2 and Caspase-3 in the apoE(−/−)iNOS(−/−) group (p<0.01), as well as in the apoE(−/−) group (p<0.05), and NF-κB, Bax in iNOS(−/−) group (p<0.05) were higher compared with WT group. However, most of the inflammatory/apoptosis parameters in the iNOS(+/−) and the apoE(+/−) groups (p>0.05) showed no differences. In addition, placenta vascular endothelial and trophoblast cell morphological changes were demonstrated in both the apoE(−/−)iNOS(−/−) and apoE(−/−) groups. CONCLUSION: Elevated lipid metabolism and inflammatory/apoptosis parameters suggest a potentially significant role of apoE in preeclampsia pathology, as well as a relationship between iNOS and preeclampsia progression.