Discovery of Carboxyethylpyrroles (CEPs): Critical Insights into AMD, Autism, Cancer, and Wound Healing from Basic Research on the Chemistry of Oxidized Phospholipids

Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, USA.
Chemical Research in Toxicology (Impact Factor: 3.53). 08/2011; 24(11):1803-16. DOI: 10.1021/tx200206v
Source: PubMed


Basic research, exploring the hypothesis that 2-(ω-carboxyethyl)pyrrole (CEP) modifications of proteins are generated nonenzymatically in vivo is delivering a bonanza of molecular mechanistic insights into age-related macular degeneration, autism, cancer, and wound healing. CEPs are produced through covalent modification of protein lysyl ε-amino groups by γ-hydroxyalkenal phospholipids that are formed by oxidative cleavage of docosahexaenate-containing phospholipids. Chemical synthesis of CEP-modified proteins and the production of highly specific antibodies that recognize them preceded and facilitated their detection in vivo and enabled exploration of their biological occurrence and activities. This investigational approach, from the chemistry of biomolecules to disease phenotype, is proving to be remarkably productive.

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    • "CEP condenses with certain amino acid residues forming covalent oxidized lipid-protein adducts [10]. Elevated levels of CEP-adducts are found in several pathological states including cancer, autistic brain tissue, atherosclerotic plaques, sites undergoing wound healing, and in AMD patients’ retinas [10]–[15]. Using a mouse model of AMD that utilizes CEP-immunization, we previously reported that in addition to signs of retinal damage mimicking AMD pathology in humans, CEP-immunized mice develop retinal infiltrating macrophages [16], [17]. In characterizing these macrophages we distinguished their polarization to be M1, not M2. "
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    ABSTRACT: Oxidative stress is key in the pathogenesis of several diseases including age-related macular degeneration (AMD), atherosclerosis, diabetes, and Alzheimer's disease. It has previously been established that a lipid peroxidation product, carboxyethylpyrrole (CEP), accumulates in the retinas of AMD patients. Retinal infiltrating macrophages also accumulate in the retinas of both AMD patients and in a murine model of AMD. We therefore investigated the ability of CEP-adducts to activate innate immune signaling in murine bone-marrow derived macrophages (BMDMs). We found that CEP specifically synergizes with low-dose TLR2-agonists (but not agonists for other TLRs) to induce production of inflammatory cytokines. Moreover, CEP selectively augments TLR2/TLR1-signaling instead of TLR2/TLR6-signaling. These studies uncover a novel synergistic inflammatory relationship between an endogenously produced oxidation molecule and a pathogen-derived product, which may have implications in the AMD disease process and other oxidative stress-driven pathologies.
    Full-text · Article · Sep 2014 · PLoS ONE
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    ABSTRACT: Basic research, exploring the hypothesis that γ-hydroxyalkenal phospholipids are generated in vivo through oxidative cleavage of polyunsaturated phospholipids, is delivering a bonanza of molecular mechanistic insights into cardiovascular disease. Rather than targeting a specific pathology, these studies were predicated on the presumption that a fundamental understanding of lipid oxidation is likely to provide critical insights into disease processes. This investigational approach, from the chemistry of biomolecules to disease phenotype, that complements the more common opposite paradigm, is proving remarkably productive.
    Full-text · Article · Aug 2011 · Chemical Research in Toxicology
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    ABSTRACT: Oxygen is essential for the growth and function of mammalian cells. However, imbalances in oxygen or abnormalities in the ability of a cell to respond to oxygen levels can result in oxidative stress. Oxidative stress plays an important role in a number of diseases including atherosclerosis, rheumatoid arthritis, cancer, neurodegenerative diseases and asthma. When membrane lipids are exposed to high levels of oxygen or derived oxidants, they undergo lipid peroxidation to generate oxidized phospholipids (oxPL). Continual exposure to oxidants and decomposition of oxPL results in the formation of reactive electrophiles, such as 4-hydroxy-2-nonenal (HNE). Reactive lipid electrophiles have been shown to covalently modify DNA and proteins. Furthermore, exposure of cells to lipid electrophiles results in the activation of cytoprotective signaling pathways in order to promote cell survival and recovery from oxidant stress. However, if not properly managed by cellular detoxification mechanisms, the continual exposure of cells to electrophiles results in cytotoxicity. The following perspective will discuss the biological importance of lipid electrophile protein adducts including current strategies employed to identify and isolate protein adducts of lipid electrophiles as well as approaches to define cellular signaling mechanisms altered upon exposure to electrophiles. This article is part of a Special Issue entitled: Oxidized phospholipids-their properties and interactions with proteins.
    Preview · Article · Apr 2012 · Biochimica et Biophysica Acta
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