Endothelial Cell Hypoxia Tolerance: Role of Plasmalogens

内皮细胞缺氧耐受性：缩醛磷脂的作用

• 批准号: 6769471
• 负责人: HARRISON W FARBER
• 金额: $ 40.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769471
• 关键词: antioxidants; biochemistry; cell membrane; free radical oxygen; hypoxia; liquid chromatography; phospholipids; plasmalogens; second messengers; thin layer chromatography; unsaturated fatty acids; vascular endothelium

DESCRIPTION (provided by applicant): We have demonstrated that endothelial cells (EC) are highly resistant to the injurious effects of acute and chronic hypoxia and have theorized that in EC, as in other hypoxia tolerant organisms or tissues, multiple factors contribute to their remarkable hypoxia tolerance. Among these potential factors are plasmalogens, a subset of "vinyl ether" phospholipids that are found within cellular membranes, constitute .18% of the total phospholipid mass in humans and have been identified as potent endogenous antioxidants. We have developed substantial evidence that plasmalogens exist in human and bovine pulmonary artery EC (HPAEC and BPAEC) and human brain microvascular EC and that increased plasmalogen levels correlate with resistance of human EC to the injurious effects of hypoxia and reactive oxygen species (ROS). Plasmalogen protection appears stress specific in that HPAEC with increased levels of plasmalogen are not protected against other common cellular stresses, such as heat shock or glucose deprivation. These findings suggest that plasmalogens can contribute to the protection of EC against specific cellular stresses; to investigate this hypothesis further, we will: 1) Define the role of plasmalogens in human EC survival during hypoxia: by establishing a relationship between plasmalogen levels and cell damage during exposure to hypoxia through modulation of plasmenylcholine content; by determining plasmalogen loss in normoxia and during exposure to hypoxia; by determining chemical breakdown, metabolic products of plasmalogens and/or plasmalogen-dependent eicosanoid products in normoxia and during hypoxia to determine if plasmalogens act as scavengers of ROS or as precursors for second messengers. 2) Define the stress-specific protection of increased human EC plasmalogen content: by comparing cell damage during exposure to hypoxia and other cellular stresses (exposure to ROS, change in redox potential, increased temperature, glucose depletion, etc): by determining the association between plasmalogens and cellular oxidants, cellular oxidases and antioxidants. Once the biochemistry of plasmalogens in EC has been clarified, studies to determine their biological importance can be undertaken.

描述（由申请人提供）：我们已经证明内皮细胞（EC）对急性和慢性缺氧的伤害性作用具有高度抵抗力，并推测内皮细胞与其他耐缺氧的生物体或组织一样，有多种因素导致其显着的表现。耐缺氧能力。这些潜在因素中包括缩醛磷脂，它是细胞膜内发现的“乙烯基醚”磷脂的一个子集，占人体总磷脂质量的 0.18%，并已被确定为有效的内源性抗氧化剂。我们已经获得大量证据表明，缩醛磷脂存在于人和牛肺动脉 EC（HPAEC 和 BPAEC）以及人脑微血管 EC 中，并且缩醛磷脂水平的升高与人类 EC 对缺氧和活性氧 (ROS) 有害影响的抵抗力相关。缩醛磷脂保护似乎具有应激特异性，因为缩醛磷脂水平升高的 HPAEC 无法抵御其他常见的细胞应激，例如热休克或葡萄糖剥夺。这些发现表明，缩醛磷脂有助于保护 EC 免受特定细胞应激的影响；为了进一步研究这一假设，我们将： 1) 定义缩醛磷脂在缺氧期间人类 EC 存活中的作用：通过调节缩醛磷脂含量，建立缩醛磷脂水平与缺氧期间细胞损伤之间的关系；通过测定常氧条件下和暴露于缺氧期间缩醛磷脂的损失；通过测定常氧和缺氧期间缩醛磷脂和/或缩醛磷脂依赖性类二十烷酸产物的化学分解、代谢产物，以确定缩醛磷脂是否充当ROS的清除剂或作为第二信使的前体。 2) 定义增加人 EC 缩醛磷脂含量的应激特异性保护：通过比较暴露于缺氧和其他细胞应激（暴露于 ROS、氧化还原电位变化、温度升高、葡萄糖消耗等）期间的细胞损伤：通过确定关联缩醛磷脂和细胞氧化剂、细胞氧化酶和抗氧化剂之间。一旦澄清了 EC 中缩醛磷脂的生物化学，就可以进行研究以确定其生物学重要性。