Praticò D, Iuliano L, Mauriello A, Spagnoli L, Lawson J A, Rokach J, Maclouf J, Violi F, FitzGerald G A
The Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 1997 Oct 15;100(8):2028-34. doi: 10.1172/JCI119735.
F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.
F2-异前列腺素是细胞膜中花生四烯酸过氧化原位形成的前列腺素（PG）异构体。8-表前列腺素F2α和异前列腺素F2α-I是人体内产生的F2-异前列腺素，它们在血浆中循环并经尿液排泄。在活性氧可能参与的临床环境中，F2-异前列腺素的测量可为测量氧化应激提供一种灵敏、特异且非侵入性的方法。我们确定了异前列腺素是否存在于人类动脉粥样硬化病变中，因为人们认为体内会发生脂质过氧化。在动脉内膜切除标本中，8-表前列腺素F2α的含量范围为1.3×10⁻³至3.450 pmol/微摩尔磷脂，而在无动脉粥样硬化的血管组织中为0.045至0.115 pmol/微摩尔磷脂（P < 0.001）。异前列腺素F2α-I的相应值分别为5.6至13.8和0.16至0.44 pmol/微摩尔磷脂（P < 0.001）。血管组织中这两种异前列腺素的水平高度相关（r = 0.80，P < 0.0001）。免疫组织化学研究证实，斑块脂质坏死核心附近的泡沫细胞对8-表前列腺素F2α呈明显阳性。这些细胞也与抗CD68反应，抗CD68是人类单核细胞/巨噬细胞特有的表位。在抗α-平滑肌肌动蛋白抗体阳性的细胞中也检测到了8-表前列腺素F2α免疫反应性，该抗体特异性识别血管平滑肌细胞。我们的结果表明，8-表前列腺素F2α和异前列腺素F2α-I这两种不同的F2-异前列腺素以及体内氧化应激的标志物存在于人类动脉粥样硬化斑块中。对这些脂质过氧化的化学稳定产物在靶组织以及生物体液中的定量分析，可能有助于合理开发人类抗氧化药物。
