Receptor-mediated mechanism controlling tissue levels of bioactive lipid oxidation products

Research output: Contribution to journalArticle


External Institution(s)

  • Cleveland Clinic Foundation
  • Case Western Reserve University


Original languageEnglish (US)
Pages (from-to)321-332
Number of pages12
JournalCirculation research
Issue number4
StatusPublished - Jul 1 2015


Rationale: 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. Objective: To identify the cellular and molecular mechanism for CEP clearance. Methods and Results: 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. F4/80hi and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared with F4/80lo 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. Conclusions: 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.

    Research areas

  • Angiogenesis inducing agents, Antigens, CD36, Macrophages, Toll-like receptor 2, Wound healing

Citation formats



Kim, YW, Yakubenko, VP, West, XZ, Gugiu, GB, Renganathan, K, Biswas, S, Gao, D, Crabb, JW, Salomon, RG, Podrez, EA & Byzova, TV 2015, 'Receptor-mediated mechanism controlling tissue levels of bioactive lipid oxidation products', Circulation research, vol. 117, no. 4, pp. 321-332.