HOMOCYSTEINE, BETA-OXIDATION AND RISK OF PREECLAMPSIA

描述(根据申请者的描述改编)：先兆子痫是 发达国家孕产妇死亡的主要原因及其增加 围产儿死亡率是五倍。先兆子痫的危险因素很多(肥胖、 高血压、胰岛素抵抗等)类似于 动脉硬化。动脉粥样硬化的另一个危险因素，同型半胱氨酸 在先兆子痫妇女的血液中也发现了增加。这个 同型半胱氨酸增加血管疾病风险的机制(S) 先兆子痫在很大程度上是未知的。最近的研究表明， 血浆同型半胱氨酸升高与胰岛素抵抗的关系。这 同型半胱氨酸与子痫前期、动脉粥样硬化和 胰岛素抵抗促使人们寻找一种共同的机制，可能是在 研究这些疾病中的每一种。胰岛素抵抗影响脂代谢 以及以关键方式促进致动脉粥样硬化的脂质代谢的β-氧化， 与内皮依赖性血管松弛降低有关，并且 增加冠状动脉和外周血管疾病的风险。这些是相同的 先兆子痫的影响已经被描述，并可能有助于 疾病的病理学。此外，基因研究表明， β-氧化的中断显著增加了先兆子痫的风险。 因此，我们推测，β-氧化减少可能是一种常见的 这些疾病之间的机制以及同型半胱氨酸对β-氧化的影响 将在先兆子痫的病理过程中发挥重要作用。我们假设： 1)高同型半胱氨酸血症易导致β-氧化降低，而这 这种影响在怀孕期间会加剧，2)在怀孕期间β-氧化减少 怀孕会使女性易患与以下疾病相关的血管并发症 先兆子痫。调查人员将通过测试来验证这些假设 先兆子痫患者β-氧化降低标志物的检测及其相关性 患者的同型半胱氨酸浓度。他们将调查是否 小鼠模型中的高同型半胱氨酸血症将影响两者的β-氧化 怀孕和未怀孕的动物。最后，调查人员将调查 药物诱导的β-氧化减少对血管紧张素转换酶的影响 未怀孕和怀孕小鼠模型的血管系统功能。这些研究 可能会使我们更好地理解(S) 高同型半胱氨酸血症增加先兆子痫的风险 对先兆子痫病理生理学的理解提示新的 治疗策略。

DESCRIPTION (Adapted from applicant's description): Preeclampsia is the leading cause of maternal mortality in developed nations and increases perinatal mortality five fold. Many risk factors for preeclampsia (obesity, hypertension, insulin resistance, etc.) are similar to those for atherosclerosis. Another risk factor for atherosclerosis, homocysteine, has also been found to be increased in the blood of women with preeclampsia. The mechanism(s) by which homocysteine increases the risk of vascular disease and preeclampsia is largely unknown. Recent studies have demonstrated a strong association between increased plasma homocysteine and insulin resistance. This inter-relatedness of homocysteine and preeclampsia, atherosclerosis and insulin resistance prompted a search for a common mechanism that may be at work in each of these diseases. Insulin resistance affects lipid metabolism and beta-oxidation in critical ways that promote an atherogenic lipid profile, is associated with decreased endothelium-dependent vasorelaxation, and increases the risk of coronary and peripheral vascular disease. These same effects have been described in preeclampsia and likely contribute to the pathology of the disease. Furthermore, genetic studies indicate that disruption of beta-oxidation significantly increases the risk of preeclampsia. Therefore, we speculate that decreased beta-oxidation may be a common mechanism among these diseases, and homocysteine's effect on beta-oxidation will play a major role in the pathology of preeclampsia. We hypothesize that: 1) Hyperhomocysteinemia predisposes toward decreased beta-oxidation, and this effect will be exacerbated in pregnancy and 2) Decreased beta-oxidation during pregnancy will predispose women toward vascular complications associated with preeclampsia. The investigators will test these hypotheses by testing preeclamptic patients for markers of decreased beta-oxidation and relate this to patient's homocysteine concentration. They will investigate if hyperhomocysteinemia in a mouse model will affect beta-oxidation in both pregnant and nonpregnant animals. Lastly, the investigators will investigate the effect of pharmacologically induced decreased beta-oxidation on vasculature function in a nonpregnant and pregnant mouse model. These studies may lead to a greater understanding of the mechanism(s) by which hyperhomocysteinemia increases the risk of preeclampsia and to a more general understanding of the pathophysiology of preeclampsia suggesting novel therapeutic strategies.