Pretreatment with Pyridoxamine Mitigates Isolevuglandin-associated Retinal Effects in Mice Exposed to Bright Light

Charvet, Casey D.; Saadane, Aïcha; Wang, Meiyao; Salomon, Robert G.; Brunengraber, Henri; Turko, Illarion V.; Pikuleva, Irina A.

doi:10.1074/jbc.m113.498832

Cited by 25 publications

(24 citation statements)

References 92 publications

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“…First, retinal protein and metabolite levels of all three cholesterol hydroxylases were determined and compared, within retina and also to the brain (Liao et al, 2011; Liao et al, 2010; Wang et al, 2012). Second, a mechanism of the retina-specific and age-dependent deterioration of CYP27A1 activity was studied and established as well as a novel strategy to combat this mechanism (Charvet et al, 2011; Charvet et al, 2013a; Charvet et al, 2013b). Third, the role of CYP27A1 and CYP46A1 in mice was evaluated by ophthalmic characterization of Cyp27a1 −/− (Omarova et al, 2012) and Cyp27a1 −/− Cyp46a1 −/− animals (manuscript in preparation).…”

Section: 0 Nr Rpe and Brmmentioning

confidence: 99%

“…The later, indirectly confirmed in a separate study demonstrating that the isoLG modification impairs CYP27A1 activity in vitro (Charvet et al, 2013a), gave impetus to the pharmacologic treatments with pyridoxamine, former dietary supplement, now an investigational new pharmaceutical, as the FDA has changed its regulatory status in 2009. Pyridoxamine, efficient scavenger of lipid peroxidation products including isoLGs (Caldes et al, 2011), was administered to mice after they were exposed to bright light to induce the formation of isoLGs (Charvet et al, 2013b). This treatment tested whether pharmacologic targeting of the downstream steps in the oxidative injury cascade, e.g.…”

Section: 0 Nr Rpe and Brmmentioning

confidence: 99%

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Cholesterol in the retina: The best is yet to come

Pikuleva

Curcio

2014

Progress in Retinal and Eye Research

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Historically understudied, cholesterol in the retina is receiving more attention now because of genetic studies showing that several cholesterol-related genes are risk factors for age-related macular degeneration (AMD) and because eye pathology studies showing high cholesterol content of drusen, aging Bruch's membrane, and newly found subretinal lesions. The challenge before us is determining how the cholesterol-AMD link is realized. Meeting this challenge will require an excellent understanding these genes’ roles in retinal physiology and how chorioretinal cholesterol is maintained. In the first half of this review, we will succinctly summarize physico-chemical properties of cholesterol, its distribution in the human body, general principles of maintenance and metabolism, and differences in cholesterol handling in human and mouse that impact on experimental approaches. This information will provide a backdrop to the second part of the review focusing on unique aspects of chorioretinal cholesterol homeostasis, aging in Bruch's membrane, cholesterol in AMD lesions, a model for lesion biogenesis, a model for macular vulnerability based on vascular biology, and alignment of AMD-related genes and pathobiology using cholesterol and an atherosclerosis-like progression as unifying features. We conclude with recommendations for the most important research steps we can take towards delineating the cholesterol-AMD link.

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Section: 0 Nr Rpe and Brmmentioning

confidence: 99%

Section: 0 Nr Rpe and Brmmentioning

confidence: 99%

Cholesterol in the retina: The best is yet to come

Pikuleva

Curcio

2014

Progress in Retinal and Eye Research

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224

227

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“…TEM and SD-OCT-These procedures were as described (72,73) and utilized a 1200EX transmission electron microscope (JEOL Ltd.) and the 840HHP SD-OCT system (Bioptigen). Tissue fixation for TEM was as described (36) and included sequential incubations in 3% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.4, 1% OsO 4 in the same buffer, 1% tannic acid in 0.05 M sodium cacodylate, pH 7.4, and 1% paraphenylenediamine in 70% ethanol.…”

Section: Cyp46a1mentioning

confidence: 99%

Retinal Hypercholesterolemia Triggers Cholesterol Accumulation and Esterification in Photoreceptor Cells

Saadane

Mast

Dao

et al. 2016

Journal of Biological Chemistry

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The process of vision is impossible without the photoreceptor cells, which have a unique structure and specific maintenance of cholesterol. Herein we report on the previously unrecognized cholesterol-related pathway in the retina discovered during follow-up characterizations of Cyp27a1 ؊/؊ Cyp46a1 ؊/؊ mice.These animals have retinal hypercholesterolemia and convert excess retinal cholesterol into cholesterol esters, normally present in the retina in very small amounts. We established that in the Cyp27a1 ؊/؊ Cyp46a1 ؊/؊ retina, cholesterol esters are generated by and accumulate in the photoreceptor outer segments (OS), which is the retinal layer with the lowest cholesterol content. Mouse OS were also found to express the cholesterol-esterifying enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT1), but not lecithin-cholesterol acyltransferase (LCAT), and to differ from humans in retinal expression of ACAT1. Nevertheless, cholesterol esters were discovered to be abundant in human OS. We suggest a mechanism for cholesterol ester accumulation in the OS and that activity impairment of ACAT1 in humans may underlie the development of subretinal drusenoid deposits, a hallmark of age-related macular degeneration, which is a common blinding disease. We generated Cyp27a1؊/؊ mice, characterized their retina by different imaging modalities, and confirmed that unesterified cholesterol does accumulate in their OS and that there is photoreceptor apoptosis and OS degeneration in this line. Our results provide insights into the retinal response to local hypercholesterolemia and the retinal significance of cholesterol esterification, which could be cell-specific and both beneficial and detrimental for retinal structure and function.

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“…In contrast, pretreatment of mice with PM, an efficient scavenger of c-ketoaldehydes (vide supra), suppressed the accumulation of retinal isoLG adducts, and morphological changes in photoreceptor mitochondria were not as pronounced as in untreated animals (18). These experiments demonstrate that preventing the damage to biomolecules by lipid peroxidation products, a novel concept in vision research, is a viable strategy to combat oxidative stress in the retina.…”

Section: Inhibition Of Proteolysis: Neurodegeneration and Glaucomamentioning

confidence: 83%

“…To test whether scavenging of isoLGs could prevent modification of retinal proteins, mice were exposed to a bright light that caused retinal isoLG-adduct formation (18). In contrast, pretreatment of mice with PM, an efficient scavenger of c-ketoaldehydes (vide supra), suppressed the accumulation of retinal isoLG adducts, and morphological changes in photoreceptor mitochondria were not as pronounced as in untreated animals (18).…”

Section: Inhibition Of Proteolysis: Neurodegeneration and Glaucomamentioning

confidence: 99%

Isolevuglandin Adducts in Disease

Salomon

2015

Antioxidants & Redox Signaling

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Significance: A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radicalinduced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences. Critical Issues: IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo. Recent Advances: The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso [4]LGE 2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Ab 1-42 . Adduction of isoLGE 2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE 2 -PE agonists that foster monocyte adhesion to endothelial cells. Future Directions: Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.

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Pretreatment with Pyridoxamine Mitigates Isolevuglandin-associated Retinal Effects in Mice Exposed to Bright Light

Cited by 25 publications

References 92 publications

Cholesterol in the retina: The best is yet to come

Cholesterol in the retina: The best is yet to come

Retinal Hypercholesterolemia Triggers Cholesterol Accumulation and Esterification in Photoreceptor Cells

Isolevuglandin Adducts in Disease

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