Coffey M J, Natarajan R, Chumley P H, Coles B, Thimmalapura P R, Nowell M, Kühn H, Lewis M J, Freeman B A, O'Donnell V B
Wales Heart Research Institute, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom.
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):8006-11. doi: 10.1073/pnas.141136098. Epub 2001 Jun 26.
12/15-Lipoxygenase (LOX) activity is elevated in vascular diseases associated with impaired nitric oxide (( small middle dot)NO) bioactivity, such as hypertension and atherosclerosis. In this study, primary porcine monocytes expressing 12/15-LOX, rat A10 smooth muscle cells transfected with murine 12/15-LOX, and purified porcine 12/15-LOX all consumed *NO in the presence of lipid substrate. Suppression of LOX diene conjugation by *NO was also found, although the lipid product profile was unchanged. *NO consumption by porcine monocytes was inhibited by the LOX inhibitor, eicosatetraynoic acid. Rates of arachidonate (AA)- or linoleate (LA)-dependent *NO depletion by porcine monocytes (2.68 +/- 0.03 nmol x min(-1) x 10(6) cells(-1) and 1.5 +/- 0.25 nmol x min(-1) x 10(6) cells(-1), respectively) were several-fold greater than rates of *NO generation by cytokine-activated macrophages (0.1-0.2 nmol x min(-1) x 10(6) cells(-1)) and LA-dependent *NO consumption by primary porcine monocytes inhibited *NO activation of soluble guanylate cyclase. These data indicate that catalytic *NO consumption by 12/15-LOX modulates monocyte *NO signaling and suggest that LOXs may contribute to vascular dysfunction not only by the bioactivity of their lipid products, but also by serving as catalytic sinks for *NO in the vasculature.
12/15-脂氧合酶（LOX）活性在与一氧化氮（·NO）生物活性受损相关的血管疾病中升高，如高血压和动脉粥样硬化。在本研究中，表达12/15-LOX的原代猪单核细胞、转染了小鼠12/15-LOX的大鼠A10平滑肌细胞以及纯化的猪12/15-LOX在脂质底物存在的情况下均消耗·NO。尽管脂质产物谱未改变，但也发现·NO对LOX二烯共轭有抑制作用。猪单核细胞对·NO的消耗被LOX抑制剂二十碳四烯酸抑制。猪单核细胞依赖花生四烯酸（AA）或亚油酸（LA）的·NO消耗速率（分别为2.68±0.03 nmol·min⁻¹·10⁶细胞⁻¹和1.5±0.25 nmol·min⁻¹·10⁶细胞⁻¹）比细胞因子激活的巨噬细胞的·NO生成速率（0.1 - 0.2 nmol·min⁻¹·10⁶细胞⁻¹）高几倍，并且原代猪单核细胞依赖LA的·NO消耗抑制了可溶性鸟苷酸环化酶的·NO激活。这些数据表明，12/15-LOX催化性消耗·NO调节单核细胞的·NO信号传导，并提示LOXs可能不仅通过其脂质产物的生物活性，还通过作为血管系统中·NO的催化汇来导致血管功能障碍。
