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Grant Abstract: Cardiovascular protection by phytosterols in dyslipidemic mothers and progeny

Grant Number: 5K01AT007826-03
PI Name: Rideout
Project Title: Cardiovascular protection by phytosterols in dyslipidemic mothers and progeny

Abstract: The purpose of my research is to advance the utility of bioactive food components as effective
prevention and therapeutic approaches to improve cardiovascular health. Central to this purpose, my overall research objective is to evaluate how specific dietary bioactive compounds protect against diet-induced dyslipidemia by modulating the molecular regulation of cholesterol and triglyceride metabolism. To this end, the global objective of my parent K01 Career Development Award is to examine the pre-clinical safety and efficacy of maternal phytosterol supplementation as a potential lipid-lowering approach for use in hypercholesterolemic pregnancies. Supraphysiological hypercholesterolemia is a pathological condition characterized by an excessive increase in maternal serum cholesterol during pregnancy. Marked gestational hypercholesterolemia exposes the fetus to atherogenic lipoproteins and produces dyslipidemic progeny with early onset arterial lesions and a predisposition for advance arterial plaques as adults. As lipid-lowering drugs are contraindicated during pregnancy, there is an unmet need to explore alternative diet-based lipid-lowering compounds that are safe and effective in ameliorating cardiovascular disease (CVD) risk factors in offspring exposed to excessive
fat and cholesterol during early development. Although there is strong scientific support that inadequate and excessive nutrient exposure during early development may underlie maladaptive health responses in adulthood, very little is known about how early exposure to health promoting bioactive compounds may protect against CVD throughout the life-course.
Phytosterols are plant-based bioactive compounds with demonstrated cholesterol lowering efficacy and a recognized safety record in both animals and humans. As a complement to the aims of our parent award, we are seeking supplemental support to strengthen our assessment of how early phytosterol exposure impacts CVD risk by incorporating an analysis of cholesterol oxidation products, novel biomarkers that regulate arterial health and lesion progression. The oxidation of cholesterol forms a wide range of oxygenated bioactive derivatives that are more commonly referred to as oxysterols. Oxysterols interact directly with specific intracellular nuclear receptors and binding proteins to regulate multiple aspects of cholesterol metabolism, arterial inflammation, and the development and regression of atherosclerotic lesions. Therefore, quantitative profiling of oxysterols within serum and arterial tissue is of particular value in accessing vascular oxidative damage and in identifying benign versus vulnerable arterial plaques. Using our established hamster model of diet-induced hypercholesterolemia, we hypothesize that offspring born to mothers supplemented with phytosterols during gestation and lactation will have a more favorable oxysterol profile in serum and arterial tissue compared with pups from unsupplemented mothers. This hypothesis is based on our findings thus far in our parent award that pups born to phytosterol-supplemented mothers are protected against
hypercholesterolemia, as demonstrated by reduced blood cholesterol (total-cholesterol, LDL-cholesterol) and lipoprotein (LDL and VLDL particle number) concentrations compared with pups from unsupplemented mothers. Adoption of this innovative oxysterol biomarker panel will complement our original study aims and lend mechanistic insight into the impact of early phytosterol exposure on atherogenesis and CVD risk analysis. As the effect of maternal phytosterol supplementation on oxysterol profiles has yet to be examined, this proposed objective is highly innovative and will address significant knowledge gaps in the dietary supplement and maternal programming fields. I have full institutional support and minimal teaching and service responsibilities that will allow me to focus on my research and training goals. Furthermore, with the support, direction, and expert

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