MCS acc Etiology: Lipid Peroxidation

[michael edward badolato jr]

A principle feature of oxidative stress is lipid peroxidation - of concern is possible atherogenicity. In the context of complexity - a treatment focused on certain factors could bring a subjective sense of improvement while atherogenic developments are silent.

The situation seems gray and complicated suggesting caution in attempts to quell all symptoms. Solutions may best be conservative - considering efficacy and safety. 

DELUCA C. ET AL. BIOLOGICAL DEFINITION OF MULTIPLE CHEMICAL SENSITIVITY FROM REDOX STATE AND CYTOKINE PROFILING AND NOT FROM POLYMORPHISMS OF XENOBIOTIC-METABOLIZING ENZYMES. TOX APPL PHARM 248:285-92 2010:

"...Both reduced and oxidized forms of glutathione were severely depleted in MCS and SMCS groups as compared to healthy controls...

...A major chemical feature of lipid peroxidation is the decomposition of polyunsaturated fatty acids to form a broad array of aldehydes such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) (Uchida 1999). 4-HNE is a stable electrophile formed during lipid peroxidation of omega-6 polyunsaturated fatty acids, namely linoleic and arachidonic acids (Marantos 2008)...

...We observed a dramatic loss of polyunsaturated fatty acids, in particular physiologically important omega-6 linoleic, alpha-linolenic, and arachidonic acids from the red blood cell membranes of MCS patients. In addition, a trend to increased levels of HNE-protein levels in MCS plasma suggested accelerated lipid peroxidation. Membrane-derived arachidonic acid may be also rapidly enzymatically oxidized by cyclooxygenase or lipoxygenases giving rise of lipid mediators of inflammation, such as prostaglandins and leukotrienes..."

 

TERLECKY S. ET AL. PEROXISOMES AND AGING. 1763;12:1749-54 2006:

"...there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset - leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific antibiotics...

...Many individuals worldwide are hypocatalasemic, not due to aging's effects, but rather to a reduction in cellular catalase expression (Eaton 1995, Wen 1988) or stability (Eaton 1995, Crawford 1988)...

...Cells from a hypocatalasemic patient (expressing approximately 25% of normal catalase levels) were found to have accumulated hydrogen peroxide and harbored age-associated pathologies (Wood 2006)..."DeLuca 2010 found catalase activity in MCS patients 30% of normal.

 

KENNEDY G. ET AL OXIDATIVE STRESS LEVELS ARE RAISED IN CHRONIC FATIGUE SYNDROME AND ARE ASSOCIATED WITH CLINICAL SYMPTOMS. FREE RAD BIOL & MED 39:584-89 2005:

"...peroxidized lipids such as 8-iso-prostaglandin F2alpha may be even more pivotal in the pathological process. 8-iso-prostaglandin F2alpha is a member of the F2 -isoprostane family and can exert potent biological activity, such as platelet activation, and act as a powerful vasoconstrictor of the peripheral vasculature (Fontana 2001, Sametz 1999)... Recall DeLuca 2010 that prostaglandins are expected elevated in MCS people.

...A further indication of the in vivo consequences of increased lipid peroxidation would be higher levels of oxidized low-density lipoproteins (oxLDL) accompanied by low levels of high density lipoproteins (HDL), which are associated with the development of atherosclerosis (Nordin Fredrickson 2003)...

...Patients with CFS have significantly elevated levels of F2 isoprostanes alongside other key markers of oxidative stress...

...F2-isoprostanes are a series of prostaglandin F2alpha isomers that are described as products of non-cyclooxygenase oxidative modifications of arachidonic acid or circulating low-density (LDL) particles that have resulted from free radical attack of cell membrane phospholipids (Fontana 2001, Longmire 1994, Lynch 1994)...

...CFS patients have a lipid profile and oxidant biology that is consistent with cardiovascular risk and the presence of high levels of F2-isoprostanes may explain some of the symptoms of the disease..."

 

YANG Y. ET AL. ENDOTHELIAL GLUTATHIONE-S-TRANSFERASE A4-4 PROTECTS AGAINST OXIDATIVE STRESS AND MODULATES iNOS EXPRESSION THROUGH NF-kB TRANSLOCATION. TOX APPL PHARM 230;2:187-96 2008:

"...Our recent work in endothelial cells and human atherosclerotic plaque showed that overexpression of glutathione-S-transferases (GSTs) in endothelium protects against oxidative damage from aldehydes such as 4-HNE... DeLuca 2010: GST activity was 50% of normal in MCS patients.

...Atherosclerosis is a complex process mediated in large part by inflammatory and oxidative mechanisms, including lipid peroxidation. One of the most plentiful products of lipid peroxidation is the alpha, beta-unsaturated carbonyl, 4-hydroxynonenal (4-HNE), which is believed to be responsible for many of the cytopathological effects observed during inflammatory and oxidative stress (Awasthi 2003, Uchida 2003, Minekura 2001)...

...We recently found that the GST isoenzyme hGSTA4-4, which detoxifies 4-HNE and exhibits high activity in vacular tissue, acts as a major defense against oxidative stress in an endothelial cell line, and is upregulated in endothelial cells overlaying the earliest stages of the human atherosclerotic plaque (Yang 2004)...

...It is generally assumed that the major NOS isotype responsible for the improvement of endothelial function during atherogenesis is the constitutively expressed eNOS. However, under chronic proinflammatory conditions, iNOS isotype is also expressed in endothelial and other cell types (Wilcox 1997). Expression of iNOS has often been assumed to play a toxic role associated with local tissue destruction, for example, during endothelial dysfunction in chronic inflammatory conditions (Steiner 1997, Buttery 1996).

Other data suggest a protective role of iNOS derived NO against oxidative stress in endothelium (Hemmrich 2003). In vivo studies indicate that eNOS and iNOS have different vasculoprotective actions against vascular lesion formation: NO derived from eNOS inhibits neointimal formation, whereas NO derived from iNOS suppresses the development of constrictive remodeling (Yogo 2000)...

...We suggest that NO derived from iNOS, which is upregulated through NF-kB activation in endothelial cells may play a protective role in the earlier stages of the atherosclerotic process. Our present data also indicate that 4-HNE inhibits iNOS and NO production by downregulating the NF-kB translocation pathway, resulting in increased ROS-mediated oxidative damage, perhaps mediated through peroxynitrite, which may contribute to chronic inflammation in the endothelium. In our experiments, mGSTA4-4 abrogates these adverse effects on isolated endothelial cells, presumably by depleting 4-HNE as well as by other, unknown means of reducing oxidative stress. Thus, the GSTs provide protection against oxidative stress in vitro and are likely to be an important defense mechanism against oxidants that act as atherogens..."

 
References

Awasthi Y. et al. Role of 4-hydroxynonenal in stress mediated apoptosis signaling. Mol Aspects Med 24:219-30 2003

Buttery L. et al. Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Invest 75:77-85 1996

Deluca C. et al. Biological definition of multiple chemical sensiti... from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes. Tox and Appl Pharm 248: 285-92 2010

Crawford D. et al. Molecular defect in human acatalasia fibroblasts. Biochem Biophys Res Commin 153:59-66 1988

Eaton J. & Ma M. Acatalasemia. In Scriver C. et al. editors. The metabolic and molecular bases of inherited disease. McGraw-Hill, NY pg 2371-83 1995

Fontana L. et al. 8-Iso-PGF2 alpha induces beta 2-integrin-mediated rapid adhesion of human polymorphonuclear neutrophils: a link between oxidative stress and ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 21;1:55-60 2001

Hemmrich K. et al. iNOS activity is essential for endothelial stress gene expression protecting against oxidative damage. J Appl Physiol 95:1937-46 2003

Kennedy G. et al. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Rad Biol & Med 39:584-89 2005.

Longmire A. et al. Effect of oxygen tension on the generation of F2-isoprostanes and malondialdehyde in peroxidizing rat liver microsomes. Biochem Pharm 47:1173-77 1994

Lynch S. et al. Formation of non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in plasma low density lipoprotein exposed to oxidative stress in vivo. J Clin Invest 93:998-1004 1994

Marantos C. et al. Inhibition of the lipopolysaccharide-induced stimulation of the members of the MAPK family in human monocytes/macrophages by 4-hydroxynonenal, a product of oxidized omega-6 fatty acids. Am J Pathol 173;4:1057-66 2008

Minekura H. et al. 4-Hydroxy-2-nonenal is a powerful endogenous inhibitor of endothelial response. Biochem Biophys Res Commun 282:557-61 2001

Nordin Fredrickson G. et al. Plasma oxidized LDL: a predictor for acute myocardial infarction. Intern Med 253;4:425-29 2003

Sametz W. et al. Vascular effects of isoprostanes after endothelial damage. Prostaglandins Leukot Essent Fatty Acids 61;6:369-72 1999

Steiner L. et al. Endothelial cells as cytotoxic effector cells: cytokine-activated rat islet endothelial cells lyse syngeneic islet cells via nitric oxide. Diabetalogia 40:150-55 1997

Terlecky S. et al. Peroxisomes and Aging. Biochim Biophys Acta 1763;12:1749-54 2006

Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lip Res 42:318-43 2003

Uchida K. et al. Activation of stress signaling pathways by the end product of lipid peroxidation. J Biol Chem 274:2234-42 1999

Wen J. et al. Diminished synthesis of catalase due to the increase in catalase mRNA in Japanese type acatalasemia. Physiol Chem Phy Med NMR 20:171-76 1988

Wilcox J. et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 17:2479-88 1997

Wood C. et al. Hypocatalasemic fibroblasts accumulate hydrogen peroxide and display age-associated pathologies. Traffic 7:97-107 2006

Yang Y. et al. Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis. Atheroscler 173:211-21 2004

Yang Y. et al. Endothelial glutathione-S-transferase A4-4 protects against oxidative stress and modulates iNOS expression through NF-kB translocation. Tox Appl Pharm 230;2:187-96 2008

Yogo K. et al. Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol 20:E96-100 2000