Kim Young-Woong, Yakubenko Valentin P, West Xiaoxia Z, Gugiu Gabriel B, Renganathan Kutralanathan, Biswas Sudipta, Gao Detao, Crabb John W, Salomon Robert G, Podrez Eugene A, Byzova Tatiana V
From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
Circ Res. 2015 Jul 31;117(4):321-32. doi: 10.1161/CIRCRESAHA.117.305925. Epub 2015 May 12.
Oxidative stress is an important contributing factor in several human pathologies ranging from atherosclerosis to cancer progression; however, the mechanisms underlying tissue protection from oxidation products are poorly understood. Oxidation of membrane phospholipids, containing the polyunsaturated fatty acid docosahexaenoic acid, results in the accumulation of an end product, 2-(ω-carboxyethyl)pyrrole (CEP), which was shown to have proangiogenic and proinflammatory functions. Although CEP is continuously accumulated during chronic processes, such as tumor progression and atherosclerosis, its level during wound healing return to normal when the wound is healed, suggesting the existence of a specific clearance mechanism.
To identify the cellular and molecular mechanism for CEP clearance.
Here, we show that macrophages are able to bind, scavenge, and metabolize carboxyethylpyrrole derivatives of proteins but not structurally similar ethylpyrrole derivatives, demonstrating the high specificity of the process. F4/80(hi) and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared with F4/80(lo) and M1-skewed macrophages. Depletion of macrophages leads to increased CEP accumulation in vivo. CEP binding and clearance are dependent on 2 receptors expressed by macrophages, CD36 and toll-like receptor 2. Although knockout of each individual receptor results in diminished CEP clearance, the lack of both receptors almost completely abrogates macrophages' ability to scavenge CEP derivatives of proteins.
Our study demonstrates the mechanisms of recognition, scavenging, and clearance of pathophysiologically active products of lipid oxidation in vivo, thereby contributing to tissue protection against products of oxidative stress.
氧化应激是从动脉粥样硬化到癌症进展等多种人类疾病的重要促成因素；然而，组织免受氧化产物影响的潜在机制却知之甚少。含有多不饱和脂肪酸二十二碳六烯酸的膜磷脂氧化会导致一种终产物2-(ω-羧乙基)吡咯（CEP）的积累，研究表明该产物具有促血管生成和促炎功能。尽管CEP在肿瘤进展和动脉粥样硬化等慢性过程中持续积累，但伤口愈合时其水平会恢复正常，这表明存在一种特定的清除机制。
确定CEP清除的细胞和分子机制。
在此，我们表明巨噬细胞能够结合、清除和代谢蛋白质的羧乙基吡咯衍生物，但不能代谢结构相似的乙基吡咯衍生物，这证明了该过程具有高度特异性。与F4/80(低)和M1偏向型巨噬细胞相比，F4/80(高)和M2偏向型巨噬细胞在CEP结合和清除方面效率更高。巨噬细胞的缺失会导致体内CEP积累增加。CEP的结合和清除依赖于巨噬细胞表达的2种受体，即CD36和Toll样受体2。虽然单个受体的敲除会导致CEP清除减少，但两种受体都缺失几乎会完全消除巨噬细胞清除蛋白质CEP衍生物的能力。
我们的研究揭示了体内脂质氧化病理生理活性产物的识别、清除和清除机制，从而有助于组织抵御氧化应激产物的影响。
