HOMOCYSTEINE, BETA-OXIDATION AND RISK OF PREECLAMPSIA

描述（改编自申请人的描述）：先兆子痫是 发达国家产妇死亡率的主要原因， 围产期死亡率五倍。 先兆子痫的许多危险因素（肥胖， 高血压、胰岛素抵抗等）与那些类似 动脉粥样硬化动脉粥样硬化的另一个危险因素，同型半胱氨酸， 在患有先兆子痫的妇女的血液中也被发现增加。的 同型半胱氨酸增加血管疾病风险的机制， 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 同型半胱氨酸与先兆子痫、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， 在这些疾病中发挥作用。胰岛素抵抗影响脂质代谢 和β-氧化的关键途径，促进动脉粥样硬化脂质分布， 与内皮依赖性血管舒张降低相关， 增加冠状动脉和外周血管疾病的风险。这些相同 在先兆子痫中已经描述了这种作用， 疾病的病理学。此外，遗传学研究表明， β-氧化的破坏显著增加先兆子痫的风险。 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 将在子痫前期的病理学中发挥重要作用。 我们假设： 1)高同型半胱氨酸血症倾向于降低β-氧化，这 影响将在怀孕期间加剧，2）在怀孕期间β-氧化减少 妊娠会使女性易患血管并发症， 先兆子痫研究人员将通过测试来验证这些假设。 先兆子痫患者的β-氧化减少的标志物，并将其与 患者的同型半胱氨酸浓度。他们会调查，如果 小鼠模型中高同型半胱氨酸血症将影响 怀孕和未怀孕的动物。最后，调查人员将调查 药理学诱导的β-氧化减少对 在非妊娠和妊娠小鼠模型中的血管功能。这些研究 可能会导致更好地了解机制（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.