Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Abstract

Exposure of plasmalogen-deficient variants of the murine cell line RAW 264.7 to short-term (0-100 min) treatment with electron transport inhibitors antimycin A or cyanide (chemical hypoxia) resulted in a more rapid loss of viability than in the parent strain. Results suggested that plasmalogen-deficient cells were more sensitive to reactive oxygen species (ROS) generated during chemical hypoxia; the mutants could be rescued from chemical hypoxia by using the antioxidant Trolox, an alpha-tocopherol analogue, and they were more sensitive to ROS generation by plumbagin or by rose bengal treatment coupled with irradiation. In addition, the use of buffers containing 2H2O greatly enhanced the cytotoxic effect of chemical hypoxia, suggesting the involvement of singlet oxygen. We used the unique enzymic deficiencies displayed by the mutants to differentially restore either plasmenylethanolamine (the major plasmalogen species normally found in this cell line) or its biosynthetic precursor, plasmanylethanolamine. Restoration of plasmenylethanolamine, which contains the vinyl ether, resulted in wild-type-like resistance to chemical hypoxia and ROS generators, whereas increasing levels of its precursor, which bears the saturated ether, had no effect on cell survival. These findings identify the vinyl ether double bond as a crucial element in cellular protection under these conditions and support the hypothesis that plasmalogens, through the vinyl ether, act as antioxidants to protect cells against ROS. These phospholipids might protect cells from ROS-mediated damage during events such as chemical hypoxia.

Ingestion of plasmalogen markedly increased plasmalogen levels of blood plasma in rats

“…A protective role against oxidative stress has been proposed, especially in cerebral and cardiac tissues in which plasmalogen levels are higher than in other tissues (4). Plasmalogen also may be an endogenous lipidemic antioxidant, as the vinyl ether double bond is sensitive to oxidative agents (5)(6)(7)(8). Further, the antioxidative effects of plasmalogen on lipoprotein (9,10) and its role in lipoprotein metabolism (11) have been reported.…”

Lipid Metabolism in Neurodegenerative Diseases

“…In addition to modulating AGPS levels, AD pathogenesis could affect pPE levels in another way. Since Ab has been shown to induce oxidative stress and pPE lipids are sensitive to oxidization due to the vinyl ether bond [74], it is likely that Ab induces decrease in pPE by oxidation of pPE. While this would suggest that pPE level decreases as a result of Ab-mediated oxidative stress and regulation of AGPS, it remains unclear whether pPE decrease could influence or accelerate the progression of AD.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…For example, while UV light-induced oxidation of plasmalogens generates aldehydes via dioxetane intermediates, Fe 2+ /ascorbate treatment results in the formation of α-hydroxy-aldehydes via plasmalogen epoxides . Plasmalogens do protect cells against chemical hypoxia induced by antimycin A or cyanide (by scavenging produced ROS), as shown in the murine monocyte/macrophage cell line RAW 264.7 (Zoeller et al, 1999) and human pulmonary arterial endothelial cells (PAEC) (Zoeller et al, 2002). During UVexposure of Chinese hamster ovary (CHO) cells photosensitized with ω-pyrene-substituted fatty acids or Merocyanine 540, plasmalogens disappear (Zoeller et al, 1988).…”

“…Cells with higher plasmalogen levels are more resistant to H 2 O 2 , hyperoxia, and the O •− 2 generator plumbagin (Zoeller et al, 2002), whereas the protective actions are gone in cells lacking plasmalogens. Photosensitisized plasmalogen-deficient CHO cells and mouse embryonic fibroblasts are hypersensitive to light treatment (Zoeller et al, 1988;Wang et al, 2013b), and plasmalogen-deficient RAW 264.7 cells are more sensitive to electron transport inhibitors (Zoeller et al, 1999). However, plasmalogens are apparently not important to protect cells against lactic acid-induced oxidative stress, at least not in primary rat astrocytes .…”