5Lipoxygenase-mediated vasculopathy in HHcy

5 HHcy 中脂氧合酶介导的血管病变

• 批准号: 8438046
• 负责人: DOMENICO PRATICO
• 金额: $ 36.89万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438046
• 关键词: Address; Aging; Amino Acids; Amyloid; Amyloid beta-Protein; Arachidonate 5-Lipoxygenase; Arteries; Biochemical; Biological Assay; Blood Vessels; Blood flow; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrum; Chronic; Coronary heart disease; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Data; Deposition; Development; Drainage procedure; Endothelial Cells; Enzymes; Epigenetic Process; Event; Extracellular Space; Folate; Functional disorder; Future; Genes; Goals; Hemorrhage; Homocysteine; Homocystine; Human; Hydrolysis; Hyperhomocysteinemia; Incidence; Inflammation; Inflammatory; Knock-out; Lesion; Link; Lymphatic; Mediating; Mediator of activation protein; Metabolic Pathway; Methionine; Methylation; Methyltransferase; Modification; Mus; Neuraxis; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Plasma; Production; Proteins; Reaction; Risk Factors; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Secondary to; Smooth Muscle Myocytes; Stimulus; Stroke; Sulfur; Testing; Time; Tissues; Translating; Up-Regulation; Vascular Diseases; Vitamin B 12; Vitamin B6; cerebral artery; cerebrovascular; in vivo; inhibitor/antagonist; mortality; mouse model; novel; promoter; public health relevance; response; vascular inflammation

DESCRIPTION (provided by applicant): Elevated levels of total plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), are associated with increased incidence and mortality of chronic vascular diseases including coronary heart disease and stroke. However, the underlying biochemical mechanisms remain unknown. HHcy results in a significant elevation of intracellular levels of S- adenosylhomocysteine (SAH), a potent endogenous inhibitor of methyl-transfer reactions. Recently, we found that HHcy up-regulates the 5-Lipoxygenase (5- LO), an enzyme abundantly present in the vasculature, where it induces an increased formation of the amyloid beta peptide (Abeta) within the endothelial cells (EC). Once formed Abeta is rapidly eliminated along perivascular lymphatic drainage pathways. However, if the total amount of Abeta produced overcomes this ability, the peptide will accumulate in the arterial walls resulting in vascular inflammation and dysfunction. With time this condition will develop in amyloid angiopathy, which is characterized by excessive Abeta deposited also in the extracellular space of the artery wall, loss of smooth muscle cells and recruitment of circulating inflammatory cells. Taken together these data suggest a possible involvement of 5-LO in the HHcy-dependent vascular dysfunction and development of amyloid angiopathy, and support our central hypothesis: HHcy results in elevated intracellular SAH which by activating 5-LO induces an over- production of Abeta and its accumulation in the vasculature with subsequent vascular inflammation, endothelial dysfunction (ED) and ultimately amyloid angiopathy. To test our hypothesis we propose 3 linked specific Aims. In the first one, we will assess 5-LO activation and its contribution to vascular inflammation, ED and amyloid angiopathy in a mouse model of HHcy, the Tg-hCBS Cbs-/- mice. In the second one, we will determine the mechanisms by which HHcy induces 5-LO upregulation, and examine the role and mechanisms by which activated 5-LO regulates Abeta formation in EC. In the third one, we will establish the role of HHcy, and 5-LO upregulation in the development of the pathological vascular phenotype of the Tg-hCBS Cbs-/- mice.

描述（由申请人提供）：血浆总同型半胱氨酸（Hcy）水平升高，称为高同型半胱氨酸血症（HHcy），与慢性血管疾病（包括冠心病和卒中）的发病率和死亡率增加相关。然而，潜在的生化机制仍然未知。HHcy导致细胞内S-腺苷高半胱氨酸（SAH）水平显著升高，SAH是甲基转移反应的有效内源性抑制剂。最近，我们发现HHcy上调5-脂氧合酶（5- LO），该酶大量存在于脉管系统中，在脉管系统中其诱导内皮细胞（EC）内淀粉样β肽（Abeta）的形成增加。一旦形成，Abeta沿着血管周围淋巴引流途径迅速消除。然而，如果产生的Abeta总量超过了这种能力，则肽将在动脉壁中积累，导致血管炎症和功能障碍。随着时间的推移，这种病症将在淀粉样血管病中发展，其特征在于过量的Abeta也沉积在动脉壁的细胞外空间中，平滑肌细胞的损失和循环炎性细胞的募集。总之，这些数据表明5-LO可能参与HHcy依赖性血管功能障碍和淀粉样血管病的发展，并支持我们的中心假设：HHcy导致细胞内SAH升高，其通过激活5-LO诱导A β的过度产生及其在血管系统中的积累，随后发生血管炎症、内皮功能障碍（艾德）和最终的淀粉样血管病。为了验证我们的假设，我们提出了3个相关的具体目标。在第一项研究中，我们将评估5-LO激活及其对HHcy小鼠模型（Tg-hCBS Cbs-/-小鼠）中血管炎症、艾德和淀粉样血管病的作用。在第二部分中，我们将确定HHcy诱导5-LO上调的机制，并研究激活的5-LO调节EC中Abeta形成的作用和机制。在第三部分中，我们将确定HHcy和5-LO上调在Tg-hCBS Cbs-/-小鼠病理性血管表型发展中的作用。