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.