A murine model of developmental programming of atherosclerosis

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Title: A murine model of developmental programming of atherosclerosis
Author: Nima Goharkhay
Abstract: Early life is increasingly being recognized as an important period of development during which environmental changes can lead to long term effects on an individual’s health . The association between poor nutrition prior to birth and an increased risk to develop coronary heart disease , hypertension and the metabolic syndrome is well established . Animal models are a central tool to investigate the details and mechanistic basis of the effects of the early life milieu . \r \nCoronary artery disease secondary to atherosclerosis remains a major cause of death in most societies . Limited human studies indicate a strong association between maternal hypercholesterolemia and increased rates of formation of atherosclerotic lesions in children . It is conceivable that exposure to a high lipid environment during intrauterine development and early postnatal life may emerge as one of the principal risk factor for premature atherosclerosis . \r \nThese studies were performed to determine the effect of maternal hypercholesterolemia on the risk of atherosclerotic lesion formation in the offspring in a homogenous small animal model . The apoprotein E (apoE ) -deficient mouse strain was chosen because of its well described propensity to spontaneously manifest hypercholesterolemia and atherosclerosis . A strong correlation between maternal hypercholesterolemia and an increase in serum cholesterol levels was revealed in chow fed heterozygous litters born to hyperlipidemic dams at both 4 and 8 months of age . In addition , 8 -month old heterozygote animals born to apoE -deficient mothers (apoE+ / -mat ) showed higher rates of atherosclerosis and evidence of liver and kidney damage as compared with their apoE+ / -pat counterparts . In contrast , at day 21 of life apoE - / -KO and apoE+ / -mat pups showed lower total cholesterol and triglyceride levels than apoE+ /+WT or apoE+ / -pat litters . \r \nStudies in liver tissue from offspring at 8 months of age suggest activation of the endogenous cholesterol synthetic pathway in apoE+ / -mat offspring . This may be one of the mechanisms responsible for the observed programming effects . In -vivo activity and blood pressure measurements and vascular reactivity experiments in 4 -month old animals did not demonstrate significant differences among study groups . No marked variation in serum cholesterol levels among genetically similar dams was detected . \r \n
URI: http : / /hdl .handle .net /2152 .3 /83
Date: 2009-03-30


A murine model of developmental programming of atherosclerosis. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /83 .

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