Red blood cell plasmalogens and docosahexaenoic acid are independently reduced in primary open-angle glaucoma
Introduction
Glaucomatous optic neuropathy is the second leading cause of blindness worldwide and will affect more than 60 million people in 2010 (Quigley and Broman, 2006). Despite extensive research, the pathogenesis of glaucoma is still not well understood. The term “glaucoma” encompasses a variety of pathophysiologic processes, all sharing the common definition of an optic neuropathy with characteristic optic nerve head remodeling and visual field defects. Primary open-angle glaucoma (POAG) is the most common form of glaucoma. Even if elevated intraocular pressure (IOP) is recognized as a major risk factor for POAG (Anderson, 1989), observations showing that elevated IOP does not lead to glaucoma and that glaucoma can develop under normal IOP conditions (Sommer et al., 1991, Drance, 1992) strongly suggest that factors other than IOP are likely to play a role in the pathogenesis of glaucomatous optic neuropathy (Pache and Flammer, 2006, Shields, 2008).
Different factors are suspected of influencing the onset and/or the progression of POAG, and it has been shown that systemic findings related to vascular disorders and blood flow occur in POAG patients more often than in healthy individuals (Flammer et al., 2002, Pache and Flammer, 2006). In addition to vasospastic factors (Flammer et al., 2001), it appears from several studies that patients with POAG have an altered hemorheology, since their red blood cells display increased aggregability and rigidity (Mary et al., 1993, Hamard et al., 1994, Vetrugno et al., 2004). Together with these data, the finding of increased erythrocyte acetylcholinesterase activity in POAG patients – which is considered an index of the alteration of membrane integrity – confirms that membrane abnormalities in red blood cells may be responsible for their altered function and deformability (Zabala et al., 1999).
Since the early 1960s, cell membranes, and particularly erythrocyte cell membranes, have been known to contain principally phospholipids (Horwitt et al., 1959, Phillips and Roome, 1959, Ways et al., 1963). These are lipidic entities consisting of a glycerol connected to two fatty acid radicals at the sn-1 and sn-2 positions and to a polar head group at the sn-3 position. Depending on the nature of the polar head, the two main classes of phospholipids are phosphatidyl-ethanolamine (PE) and phosphatidyl-choline (PC). Like other tissues or cell types, red blood cell phospholipids also consist of other phospholipids called plasmalogens, which have a fatty alcohol radical and a vinyl-ether bond at the sn-1 position of glycerol instead of a fatty acid radical (Nagan and Zoeller, 2001). As with conventional phospholipids, plasmalogens are classified according to their sn-3 position, with the most abundant plasmalogens being plasmenyl-ethanolamine (PlsE) and plasmenyl-choline (PlsC). Although the exact functions of plasmalogens remain unclear, their involvement in membrane dynamics has been largely documented by biophysical and biochemical research (Hermetter et al., 1989, Glaser and Gross, 1995). Plasmalogens facilitate membrane fluidity because of the presence of the vinyl-ether bond at the sn-1 position as well as the preferential esterification of polyunsaturated fatty acids (PUFAs) at their sn-2 position (Sugiura et al., 1983, Ford and Gross, 1989b, Ford and Gross, 1989a). Indeed, it is clearly established that PUFAs and particularly those from the omega-3 family, such as docosahexaenoic acid (DHA, 22:6ω3), enhance cell membrane flexibility owing to their multiple double bonds (Stillwell and Wassall, 2003).
One study has shown reduced levels of omega-3 PUFAs in the erythrocyte membranes of patients with POAG, which may partly explain their increased rigidity and aggregability (Ren et al., 2006). However, this study did not consider plasmalogens that may also affect erythrocyte membrane structure and function, or whether these modifications were associated with glaucoma stage. Consequently, the purpose of the present investigation was to determine the complete phospholipid composition of erythrocyte membranes in POAG patients. The second objective of this study was to see whether the changes were related to glaucoma stage.
Section snippets
Glaucoma subject selection
The data for this study were obtained under research protocols approved by the Ethics Committee of Burgundy (France). Informed consent was obtained from all subjects before participation. The procedures adhered to the tenets of the Declaration of Helsinki for human experimentation.
Consecutive POAG patients (n = 31) and control subjects (n = 10) were enrolled in the study at the Department of Ophthalmology of the University Hospital in Dijon (France) (Table 1). None of the subjects was related
Determination of the sn-positions of phospholipids by ESI-MSn
The sn-1 and sn-2 radicals of phospholipids were determined in an MSn experiment using ESI in the negative mode. We used commercially asymmetrical PE and PC standards where fatty acids in the sn-1 and sn-2 positions were identified. When operated in the single-stage MS mode using ESI in the negative mode, PE and PC molecular species produced abundant [M − H]− and [M − CH3]− ions, respectively. Using trap ion mass spectrometer in the MSn mode, the PE species have a characteristic fragmentation.
Discussion
Two major theories have been postulated to explain the pathophysiology of glaucomatous optic neuropathy: the mechanical theory and the vascular theory (Fechtner and Weinreb, 1994). The mechanical theory considers glaucomatous optic neuropathy a direct consequence of increased IOP, which leads to physical damage of the lamina cribrosa and retinal neurons (Burgoyne et al., 2005). The vascular theory assumes that glaucomatous optic neuropathy is a consequence of abnormal blood supply caused by
Funding
This study was supported by a grant from University Hospital in Dijon, France (Programme Hospitalier de Recherche Clinique, Direction de la Recherche Clinique).
Commercial relationships
None.
Acknowledgements
The authors are highly indebted to Prof. Balwantray Chauhan for his helpful advice in preparing this manuscript. They gratefully acknowledge Françoise Candé for excellent management of human sample preparation and Linda Northrup for editing the manuscript.
References (64)
Glaucoma: the damage caused by pressure. XLVI Edward Jackson memorial lecture
Am. J. Ophthalmol.
(1989)- et al.
Oxidative and nitrative stress markers in glaucoma
Free Radic. Biol. Med.
(2008) - et al.
The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage
Prog. Retin. Eye Res.
(2005) - et al.
The effects of dietary omega-3 polyunsaturated fatty acids on erythrocyte membrane phospholipids, erythrocyte deformability and blood viscosity in healthy volunteers
Atherosclerosis
(1985) Diversity of group types, regulation, and function of phospholipase A2
J. Biol. Chem.
(1994)- et al.
Composition of phospholipids and of phospholipid fatty acids and aldehydes in human red cells
J. Lipid Res.
(1967) Human erythrocyte phosphoglycerides. I. Quantification of plasmalogens, fatty acids and fatty aldehydes
Biochim. Biophys. Acta
(1962)- et al.
DHA-enriched phospholipid diets modulate age-related alterations in rat hippocampus
Neurobiol. Aging
(2003) - et al.
Mechanisms of optic nerve damage in primary open angle glaucoma
Surv. Ophthalmol.
(1994) - et al.
Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye
Prog. Retin. Eye Res.
(2001)
The impact of ocular blood flow in glaucoma
Prog. Retin. Eye Res.
Influence of plasmalogen deficiency on membrane fluidity of human skin fibroblasts: a fluorescence anisotropy study
Biochim. Biophys. Acta
Differential tissue dose responses of (n-3) and (n-6) PUFA in neonatal piglets fed docosahexaenoate and arachidonoate
J. Nutr.
Plasma and red blood cell fatty acid values as indexes of essential fatty acids in the developing organs of infants fed with milk or formulas
J. Pediatr.
Quantitative determination of phospholipid compositions by ESI-MS: effects of acyl chain length, unsaturation, and lipid concentration on instrument response
J. Lipid Res.
The effect of storage on the fatty acid composition of human serum
Clin. Chim. Acta
Topical beta-blockers and mortality
Ophthalmology
Plasmalogens: biosynthesis and functions
Prog. Lipid Res.
A sick eye in a sick body? Systemic findings in patients with primary open-angle glaucoma
Surv. Ophthalmol.
Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids
Prostaglandins Leukot. Essent. Fatty Acids
The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina
Prog. Retin. Eye Res.
Docosahexaenoic acid: membrane properties of a unique fatty acid
Chem. Phys. Lipids
Age-related changes in deformability of human erythrocytes
Blood
Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences
Prog. Retin. Eye Res.
The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase
J. Biol. Chem.
Dramatic increase of alpha-hydroxyaldehydes derived from plasmalogens in the aged human brain
Chem. Phys. Lipids
Identification of neutral active phospholipase C which hydrolyzes choline glycerophospholipids and plasmalogen selective phospholipase A2 in canine myocardium
J. Biol. Chem.
Effects of aging and dietary n-3 fatty acids on rat brain phospholipids: focus on plasmalogens
Lipids
Aminophospholipid asymmetry: a matter of life and death
Annu. Rev. Physiol.
Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: the Proctor Lecture
Invest. Ophthalmol. Vis. Sci.
Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing
J. Nutr. Health Aging
Estimating the rate of progressive visual field damage in those with open-angle glaucoma, from cross-sectional data
Invest. Ophthalmol. Vis. Sci.
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