Department of Ophthalmology, Harvard Medical School, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Sci Transl Med. 2011 Feb 9;3(69):69ra12. doi: 10.1126/scitranslmed.3001571.
Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. We have previously demonstrated that diets enriched in ω-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglial-derived tumor necrosis factor-α. To better understand the protective effects of ω-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. ω-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary ω-3 PUFAs. This protective effect was due to 5-LOX oxidation of the ω-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4-HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor γ (PPARγ), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that ω-3 PUFAs may be profitably used as an alternative or supplement to current anti-vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of ω-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary ω-3 PUFA.
脂质信号在许多伴有血管病变的疾病中失调，包括癌症、糖尿病性视网膜病变、早产儿视网膜病变和年龄相关性黄斑变性。我们之前已经证明，富含 ω-3 多不饱和脂肪酸 (PUFA) 的饮食可有效减少氧诱导性视网膜病变小鼠模型中的病理性视网膜新生血管形成，部分原因是代谢产物可抑制小胶质细胞衍生的肿瘤坏死因子-α。为了更好地了解 ω-3 PUFAs 的保护作用，我们研究了主要脂质代谢途径及其产物在促成这种作用中的相对重要性。给缺乏每个关键脂质加工酶（环氧化酶 1 或 2 或脂氧合酶 5 或 12/15）的四条小鼠品系喂食 ω-3 PUFA 饮食，通过氧暴露诱导视网膜病变；只有脂氧合酶 5 (5-LOX) 的缺失才会破坏 ω-3 PUFAs 饮食对视网膜病变的保护作用。这种保护作用归因于 5-LOX 将 ω-3 PUFA 脂质二十二碳六烯酸氧化为 4-羟基二十二碳六烯酸 (4-HDHA)。4-HDHA 通过过氧化物酶体增殖物激活受体 γ (PPARγ) 直接抑制内皮细胞增殖和发芽血管生成，与 4-HDHA 的抗炎作用无关。我们的研究表明，ω-3 PUFAs 可用作抗血管内皮生长因子 (VEGF) 治疗增生性视网膜病变的替代或补充，并且指向了 ω-3 PUFAs 和代谢物在其他血管增生性疾病中的治疗潜力。它还表明，环氧化酶抑制剂（如阿司匹林和布洛芬）（而不是脂氧合酶抑制剂，如齐留通）可在不失去饮食 ω-3 PUFA 有益作用的情况下使用。
