MG2+ MODULATION OF MEMBRANE PHOSPHOLIPID OXIDATION

MG2 调节膜磷脂氧化

• 批准号: 2764003
• 负责人: GENE A MORRILL
• 金额: $ 10.02万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2764003
• 关键词: atherosclerosis; cryoprotective agents; disease /disorder proneness /risk; electron spin resonance spectroscopy; extracellular; free radical oxygen; laboratory rat; magnesium ion; membrane lipids; mitogens; nuclear magnetic resonance spectroscopy; peroxidation; phospholipids; platelet activating factor; vascular smooth muscle

This research proposal is designed to investigate the mechanisms through which low serum Mg2+ contributes to the development of cardiovascular disease. Epidemiological studies have shown that decreased dietary intake of magnesium (Mg) is associated with increased risk for cardiovascular disease, and clinical studies show significant reductions in free ionized Mg2+ (not total Mg) in serum of patients hospitalized with cardiovascular problems. Low extracellular Mg2+ has been shown to increase vascular contractility. Our studies with vascular smooth muscle cell in vitro have shown that lowering extracellular free Mg2+ within the pathophysiological range also produces an increase in membrane lipid oxidation, in fatty acid saturation, and in the transcription factor, nuclear factor kappa B (NF-KB). The observed fatty acid changes appear due to oxygen free radical oxidation of double bonds of the fatty acids in the sn-2 (middle carbon of glycerol) position to form platelet- activating factor (PAF) like lipids. Ceramide, a sphingomyelin-derived second messenger, may be responsible for the increased NF-KB levels in these smooth muscle cells. This factor regulates genes involved in the inflammatory response, considered to be a central element of atherogenesis. These results indicate that Mg2+ protects against oxidative damage to membrane lipids. Vascular smooth muscle cells apparently respond to an atherogenic stimulus independently, and thus could amplify or modify signals from endothelial cells. We will measure in vitro changes in membrane lipid oxidation, in PAF-like lipids during atherogenesis and in oxygen free radical formation as a function of[Mg2+]0 in aortic segments and in cultured aortic smooth muscle and endothelial cells. PAF-like lipids will be isolated and identified and tested for their mitogenic activity on smooth muscle cells. We will test the hypothesis that an increase in intracellular ionized Ca2+ is responsible for increased reactive oxygen species as extracellular Mg2+ is lowered within the pathophysiological range. It is clear that low extracellular Mg2+ is a risk factor which contributes to cardiovascular pathology, and that an understanding of its mechanism of action should provide increased opportunities for arresting the complex process of atherogenesis.

该研究建议旨在研究低血清MG2+有助于心血管疾病发展的机制。流行病学研究表明，镁（MG）的饮食摄入量降低与心血管疾病的风险增加有关，临床研究显示，在患有心血管疾病的患者的血清中，自由电离MG2+（不是总MG）的显着降低。细胞外MG2+较低可增加血管收缩力。我们在体外对血管平滑肌细胞的研究表明，在病理生理范围内降低细胞外不含MG2+的研究还会导致膜脂质氧化，脂肪酸饱和度和转录因子的核因子Kappa B（NF-KB）的增加。观察到的脂肪酸变化出现，是由于Sn-2（甘油中碳）位置中脂肪酸双键的氧自由基氧化，形成血小板激活因子（PAF），如脂质。神经酰胺是鞘磷脂衍生的第二信使，可能是这些平滑肌细胞中NF-KB水平升高的原因。该因子调节涉及炎症反应的基因，被认为是动脉粥样硬化的核心元素。这些结果表明，MG2+可预防对膜脂质的氧化损伤。血管平滑肌细胞显然对动脉粥样硬化刺激有反应，因此可以扩大或修改内皮细胞的信号。我们将在动脉粥样硬化期间和氧气自由基形成过程中的膜脂质氧化，PAF样脂质中的体外变化，在主动脉片段和培养的主动脉平滑肌和内皮细胞中的[MG2+] 0的函数。 PAF样脂质将被分离，鉴定并测试其在平滑肌细胞上的有丝分裂活性。我们将检验以下假设：随着细胞外MG2+在病理生理范围内降低细胞外MG2+，细胞内电离Ca2+的增加是导致活性氧的增加。显然，低细胞外MG2+是有助于心血管病理的危险因素，并且对其作用机理的理解应为阻止复杂的动脉粥样硬化过程提供更多的机会。