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Smoking-induced generation of oxidized phospholipids and the effect of deficiency of hydrolyzing enzyme for oxidatively modified phospholipids : role of the enzyme deficiency in carcinogenesis and vascular injury.

吸烟引起的氧化磷脂的生成以及氧化修饰磷脂水解酶缺乏的影响：酶缺乏在致癌和血管损伤中的作用。

基本信息

批准号：
11670360
负责人：
SATOH Kei
金额：
$ 1.92万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Platelet-activating factor (PAF) is a bioactive phospholipid that has agonistic activities towards many types of cells such as white blood cells, smooth muscle cells, and neuronal cells ; and it is implicated various pathological conditions. Oxidation of ether phospholipids results in the generation of derivatives with a sn-2 short chain residue, and such derivatives also acquire PAF-like bioactivities. PAF or PAD-like lipids are inactivated by PAF acetylhydrolase (PAF-AH), and a high level of activity is found in plasma. Plasma PAF-AH deficiency is due to a missense mutation in the gene (G994T) and its prevalence among a general Japanese population is reported to be about 4%. This mutation is also known to be a genetic risk factor of stroke or ischemic heart disease.In the present study, we first found that the prevalence of plasma PAF-AH deficiency is virtually the same between healthy habitual smokers and non-smokers. There was no significant difference in the prevalence of the mutant gene between the group of the subjects who have risk factors for vascular diseases such as hypertension, diabetes mellitus, or hyperlipidemia (risk factor group) as compared to the group without such risk factors (normal group). However, among the subjects with normal genotype, the risk factor group had higher PAF-AH activity than the normal group. Such a difference was not observed for the subjects with the heterozygous genotype. Secondly, we detected an aggregating activity in lipid extracts of plasma obtained shortly after smoking cigarettes, and such activity co-migrated with authentic PAF in thin-layer chromatography.We conclude that plasma PAF-AH is increased in various diseases, including chronic lifestyle diseases, as an adoptive mechanism and the deficiency of this enzyme may be associated with enhanced risk for the diseases.

血小板活化因子（Platelet-activating factor，PAF）是一种具有生物活性的磷脂，对白色血细胞、平滑肌细胞、神经细胞等多种细胞具有激动作用，与多种病理状态有关。醚磷脂的氧化导致生成具有sn-2短链残基的衍生物，并且此类衍生物还获得PAF样生物活性。PAF或PAD样脂质被PAF乙酰水解酶（PAF-AH）灭活，并且在血浆中发现高水平的活性。血浆PAF-AH缺乏症是由于基因（G994 T）中的错义突变所致，据报道其在日本普通人群中的患病率约为4%。在本研究中，我们首次发现，在健康的习惯性吸烟者和非吸烟者之间，血浆PAF-AH缺乏症的患病率几乎相同。具有高血压、糖尿病、高脂血症等血管疾病的危险因素的受试者组（危险因素组）与不具有这些危险因素的受试者组（正常组）相比，突变基因的流行率没有显著差异。而基因型正常者中，危险因素组的PAF-AH活性高于正常组。在杂合子基因型受试者中未观察到这种差异。其次，我们检测到的聚集活动后不久获得的血浆中的脂质提取物吸烟，和这样的活动共同迁移与正宗的PAF在薄层chromatography.We的结论，血浆PAF-AH增加在各种疾病，包括慢性生活方式疾病，作为一种过继机制，这种酶的缺乏可能与疾病的风险增加。