SMALL, DENSE LDL IN THE PATHOGENESIS OF PREECLAMPSIA

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Preeclampsia is the leading cause of maternal death and increases perinatal mortality five-fold. Although the mechanisms underlying preeclampsia remain a mystery, compelling evidence indicates that dysfunction of the vascular endothelium is central to the disorder. The long term goal of the proposed research is to understand how alterations in lipid metabolism contribute to adverse changes in vascular function in preeclampsia. Clinically evident preeclampsia is preceded by marked hypertriglyceridemia. Metabolic changes producing elevated triglycerides can also shift the low-density lipoprotein (LDL) subfraction spectrum toward predominance of smaller, denser LDL. Small dense LDL has several altered physical properties capable of promoting endothelial cell dysfunction, including increased susceptibility to oxidative modification. Preliminary Data presented in this proposal demonstrates that a shift toward smaller, denser LDL occurs in preeclampsia relative to normal pregnancy. The hypothesis to be tested is that small dense LDL subspecies with increased oxidation susceptibility are present in greater absolute quantity and greater proportion in preeclampsia, and that these changes antedate clinically evident illness and resolve post partum. The strategy is to perform a longitudinal, nested case control study of particle diameter and oxidation susceptibility of LDL from nulliparous preeclamptics and gestationally matched controls. Thus, Aim 1 is to profile LDL particle size subclasses during gestation and 6 weeks post partum. Density gradient centrifugation is used to isolate LDL from plasma. Gradient gel electrophoresis is used to determine the predominant particle diameter in each sample. LDL is resubjected to density centrifugation to separate 6 distinct LDL subfractions. LDL mass in each subfraction is measured and the peak particle diameter of the predominant (by mass) subfraction is determined. Aim 2 is to analyze the oxidation kinetics of unfractionated LDL and predominant LDL subfractions during exposure of the isolated LDL to free radicals generated in vitro. At the conclusion of these experiments we will know whether preeclampsia is associated with a shift in LDL subclass patterns toward predominance of smaller, denser and more oxidation susceptible LDL. We will know if these changes are likely to be involved in pathogenesis (if increased before evident disease and resolved postpartum). The study will comprise a foundation for future research on adverse effects of abnormal LDL in preeclampsia.