Fetal Determinants of Atherosclerosis

动脉粥样硬化的胎儿决定因素

• 批准号: 6701813
• 负责人: WULF PALINSKI
• 金额: $ 48.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701813
• 关键词: antihypercholesterolemic agent; antioxidants; atherosclerosis; cardiovascular disorder chemotherapy; developmental genetics; disease /disorder model; disease /disorder onset; gene expression; genetic susceptibility; hypercholesterolemia; immunocytochemistry; laboratory mouse; laboratory rabbit; laser capture microdissection; lipid peroxides; low density lipoprotein; low density lipoprotein receptor; microarray technology; model design /development; naphthalenes; nonhuman therapy evaluation; nuclear factor kappa beta; oxidative stress; peroxisome proliferator activated receptor; polymerase chain reaction; protein quantitation /detection

DESCRIPTION (provided by applicant): We previously showed that atherogenesis already begins during fetal development and that maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in fetuses and a much faster progression of atherosclerosis in normocholesterolemic children that could not be explained by conventional risk factors. Although in humans inherited genetic differences are likely to contribute, we hypothesize that maternal hypercholesterolemia per se induces pathogenic events in fetal arteries that determine their later susceptibility to atherosclerosis. We also hypothesize that oxidative stress caused by maternal hypercholesterolemia leads to persistent changes in the expression of genes modulating atherogenesis. An important corollary is that cholesterol lowering and antioxidant interventions in mothers during pregnancy may provide long-lasting benefits to their offspring. Using genetically homogeneous animal models, we recently provided direct evidence for the causal role of maternal hypercholesterolemia and oxidative stress in both enhanced fetal lesion formation and accelerated post-natal atherogenesis. We also provided proof in principle for persistent regulation of gene expression in the arterial wall. We now propose to better define the in utero programming associated with maternal hypercholesterolemia, to identify genes influencing post-natal susceptibility to atherosclerosis, and to investigate whether interventions during pregnancy also decrease the susceptibility in offspring of "normocholesterolemic" mothers. Different levels of maternal hypercholesterolemia and antioxidant protection will be achieved by transferring embryos of LDL receptor deficient (LDLR-/-) mice into treated or untreated C57BL/6, LDLR -/- or apoE -/- mice. Offspring will be subjected to post-natal atherogenic conditions and lesion formation followed over time. Laser-capture microdissection, gene microarray and PCR techniques will be used to determine persistence of gene regulation and its correlation with atherosclerosis, immunocytochemical presence of gene products and measurements of oxidative stress. These studies should yield fundamentally new insights into in utero programming and atherogenic mechanisms, and may establish a novel preventive approach.

描述（由申请人提供）：我们之前表明，动脉粥样硬化在胎儿发育期间就已经开始，并且怀孕期间母体高胆固醇血症与胎儿脂肪条纹形成增强以及正常胆固醇儿童动脉粥样硬化进展更快有关，而这无法用传统的危险因素来解释。尽管在人类中遗传的基因差异可能有所贡献，但我们假设母体高胆固醇血症本身会诱发胎儿动脉的致病事件，从而决定其以后对动脉粥样硬化的易感性。我们还假设母体高胆固醇血症引起的氧化应激会导致调节动脉粥样硬化形成的基因表达的持续变化。一个重要的推论是，母亲在怀孕期间进行降低胆固醇和抗氧化干预可能会给她们的后代带来持久的好处。最近，我们利用遗传同质的动物模型，提供了直接证据，证明母体高胆固醇血症和氧化应激在增强胎儿病变形成和加速产后动脉粥样硬化形成中的因果作用。我们还为动脉壁基因表达的持续调节提供了原则上的证据。我们现在建议更好地定义与母亲高胆固醇血症相关的子宫内编程，以确定影响产后动脉粥样硬化易感性的基因，并研究怀孕期间的干预措施是否也会降低“正常胆固醇血症”母亲的后代的易感性。通过将 LDL 受体缺陷 (LDLR-/-) 小鼠的胚胎移植到治疗或未治疗的 C57BL/6、LDLR -/- 或 apoE -/- 小鼠中，可以实现不同水平的母体高胆固醇血症和抗氧化保护。后代将遭受出生后动脉粥样硬化的影响，并随着时间的推移形成病变。激光捕获显微切割、基因微阵列和PCR技术将用于确定基因调控的持续性及其与动脉粥样硬化的相关性、基因产物的免疫细胞化学存在以及氧化应激的测量。这些研究应该对子宫内编程和动脉粥样硬化机制产生根本性的新见解，并可能建立一种新的预防方法。