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Supplement

Vitamin E and Macrophage Cyclooxygenase Regulation in the Aged^{1 ,2}

Dayong Wu^*,, Michael G. Hayek^** and Simin Nikbin Meydani^*3

^* Nutritional Immunology Laboratory, Jean Mayer Human Research Center on Aging at Tufts University, Boston, MA 02111; Department of Immunology, Norman Bethune University of Medical Sciences, Changchun, China; and ^** Iams Company, Lewisburg, OH 45338

³To whom correspondence should be addressed. E-mail: SMeydani{at}hnrc.tufts.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

 
Aging is associated with increased evidence of cardiovascular disease (CVD). Atherosclerosis, a major cause of CVD, is an inflammatory process whose development is influenced by several proinflammatory mediators. Products of arachidonic acid metabolism, in particular, prostaglandin (PG) E₂ and thromboxane (TX) A₂, play an important role in the development of atherosclerosis. We showed previously that the aged have higher PGE₂ production compared with their young counterparts. This age-associated increase in PGE₂ production is mainly a consequence of increased cyclooxygenase (COX) activity. We demonstrated further that increased COX activity in old mice is due to the increased expression of mRNA and protein for the inducible form of COX, COX-2. Vitamin E has been shown to reduce PGE₂ production and risk of CVD. In aged mice, we showed that a vitamin E–induced decrease in PGE₂ production is due to decreased COX activity. However, vitamin E had no effect on COX mRNA and protein levels, indicating a post-translational regulation of COX by vitamin E. Further experiments indicated that vitamin E decreases COX activity through reducing formation of peroxynitrite, a hydroperoxide shown to be involved in the activation of COX-2. Other homologues of tocopherols were also effective in inhibiting COX activity, but their degree of inhibition varied. The varied potency to inhibit COX activity was not explained totally by differences in their antioxidant capacity. Vitamin E–induced inhibition of COX activity might contribute to its effect of reducing CVD risk.

KEY WORDS: • vitamin E • cardiovascular disease • atherosclerosis • prostaglandin

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

 
Several lines of evidence support the notion that atherosclerosis is an inflammatory disease (Alexander 1994 , Ross 1993 ). A relationship between markers of inflammation such as c-reactive protein and risk of myocardial infarction was demonstrated (Liuzzo et al. 1994 , Ridker et al. 1997 ). Plaque rupture leading to thrombosis is the key event in infarction and has been shown to be related to increased inflammation within the plaque (van der Wal et al. 1994 ). Reduction in the inflammatory response may be associated with a reduction in the risk of subsequent ischemic events, and the beneficial effect of aspirin in reducing the risk of myocardial infarction has been suggested to be attributable in part to its anti-inflammatory action (Alexander 1994 , Ridker et al. 1997 ).

Eicosanoids in general, and monocyte/macrophage eicosanoids, such as prostaglandin (PG)⁴ E₂ and thromboxane (TX) B₂ in particular, contribute to the pathogenesis of cardiovascular diseases (CVD) through proinflammatory and proaggregatory activities. Eicosanoids are formed from arachidonic acid (AA) in membrane phospholipids through the function of the enzyme cyclooxygenase (COX) (Fig. 1 ). The first step in the conversion of AA to PGE₂ is the formation of PG endoperoxide (PGH₂) by dual cyclooxygenase and peroxidase function of PGH synthetase. The PGH₂ formed is then isomerized enzymatically to PGE₂ or other COX products depending on the cell type. COX enzymatic activity is the rate-limiting step in the production of PGE₂. The activity of COX is determined by the level of the enzyme and requires the presence of oxidant hydroperoxide as an activator. At least two forms of the enzyme COX exist, a constitutive (COX-1) and an inducible (COX-2) form. COX-1 is constitutively expressed and is involved mainly in control of normal physiologic functions, whereas COX-2 is regulated by growth factors, tumor promoters, cytokines, glucocorticoids and lipopolysaccharide (LPS). Overexpression of COX-2 has been indicated in the pathogenesis of inflammatory and neoplastic diseases. In recent years, a role for COX-2 in the pathogenesis of atherosclerosis has been defined. COX-2 is involved in inflammatory response via rapid and excessive production of prostanoids, which have proatherosclerotic effects. A COX-dependent, aspirin-reversible constricting factor was shown to contribute to the endothelial cell dysfunction in atherosclerosis (Husain et al. 1998 ). Cytomegalovirus (CMV) has been suggested to contribute causally to restenosis and atherosclerosis. CMV was shown to increase production of reactive oxygen species through a COX-2 dependent pathway (Speir et al. 1998 ). COX-2 in activated human monocytes generates the isoprostane 8-epi-PGF₂, which is mitogenic and vasoactive (Yan et al. 2000 ). COX-2 is expressed in atherosclerotic lesions, increases after vascular injury and has been detected in myocardia of patients with congestive heart failure. Monocyte-derived prostaglandins decreased the secretion of procollagen by human vascular smooth muscle cells by 60%. This can result in reduced plaque stability and plaque rupture (Fitzsimmons et al. 1999 ).

View larger version (31K): [in this window] [in a new window]   Figure 1. Arachidonic acid metabolism cascade. Arachidonic acid (AA) is released from membrane phospholipids under action of phospholipase A2. AA is metabolized to prostaglandin (PG)H2 by cyclooxygenase (COX). COX has bifunctional catalytic properties, i.e., catalyzing both formation of PGG2 from AA via its cyclooxygenase activity and subsequent reduction of PGG2 to PGH2 via its peroxidase activity. PGH2 will be converted to different PG and thromboxane (TX) A2 by the action of different isomerases. COX is the rate-limiting enzyme in the biosynthesis of PG. AA can also be metabolized to various hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT) by the corresponding lipoxygenases (LO).

Benzo(a)pyrene, present in tobacco smoke and tar, has been implicated in the development of atherosclerosis as well as cancer. Increased expression of COX-2 has been detected in both atherosclerotic lesions and epithelial cancers. Yan et al. (2000) showed that benzo(a)pyrene increased expression (protein and mRNA) of COX-2 in vascular cells (human and rat arterial smooth muscle cells) and increased prostaglandin synthesis. Rimarachin et al. (1994) showed that mechanical injury induced COX-2 in vascular tissue and increased expression of COX-2 presented within vascular smooth muscle cells during development of proliferative lesions in the injured vessels. High levels of COX-2 in epithelial cells are associated with the inhibition of apoptosis. In the development of atherosclerotic plaques, it is possible that a similar antiapoptotic effect of high levels of COX-2 could augment plaque growth by decreasing cell death rates and depressing normal vascular remodeling. Collectively, these data suggest that COX-2 and its AA-generated products may participate in the initiation and pathogenesis of atherosclerosis.

	Upregulation of PGE2 production with age

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

 
Several lines of evidence have suggested that eicosanoid production is altered with age. These have included increased PGE₂ production from cultured adherent cells or spleen homogenates from old mice (Meydani et al. 1990b , Rosenstein and Strauser 1980 ) cultured mononuclear cells from elderly humans (Meydani et al. 1990a ), kidney homogenates from old rats (Kim et al. 2000 ), urinary prostaglandin metabolites from older adults (Vericel et al. 1988 , Wilson et al. 1989 ) and lung homogenates from old mice (Meydani et al. 1992 ). These data collectively suggest an alteration of eicosanoid synthesis during aging.

Eicosanoids generated from the AA cascade can result in a variety of metabolites, which are generated by several enzymes (Fig. 1) . To determine whether aging upregulates the production of all or specific eicosanoid metabolites, a series of studies was conducted to characterize alterations in eicosanoid production with age (Hayek et al. 1994 ). Splenocytes were isolated from young (4 mo) and old (24 mo) mice and challenged with Ca⁺⁺ ionophore or concanavalin A (ConA). As shown in Table 1 , there was no difference in 12- or 15-hydroxyeicosatetraenoic acid (HETE) production between the two ages; however, there was an increase in leukotriene (LT) B₄, LTC₄ and PGE₂ production in old mice compared with young mice. The data presented in Table 1 are for stimulation with CA⁺⁺ ionophore. Similar results were observed when the splenocytes were stimulated with ConA. This suggested that the age-associated increase in eicosanoid synthesis was specific to the 5-lipoxygenase (LTB₄ and LTC₄) and cyclooxygenase (PGE₂) enzymes. We further showed that the COX metabolite (PGE₂) and not the 5-lipoxygenase products contributed to the decline in T-cell–mediated function observed in the elderly (Beharka et al. 1997 , Hayek et al. 1994 ).

View larger version (13K): [in this window] [in a new window]   Figure 2. Prostaglandin (PG)E2 production (A) and cyclooxygenase (COX) activity (B) in peritoneal macrophages (M) from young and old C57BL/6NIA mice. M were incubated in the presence of 5 µg/mL lipopolysaccharide for different lengths of time as indicated. PGE2 in the supernatants was determined by RIA. COX activity was determined by measuring PGE2 production from 30 µmol/L exogenous AA within 10 min. Results are means ± SEM, n = 10. *Significantly different from young mice at P < 0.01. Data adapted from Hayek et al. (1997) .

View larger version (23K): [in this window] [in a new window]   Figure 3. Cyclooxygenase (COX) mRNA (A) and protein (B) expression in peritoneal macrophages (M) from young and old C57BL/6NIA mice. M were incubated in the presence of 5 µg/mL lipopolysaccharide for different lengths of time as indicated. COX mRNA was assessed by RNase protection assay. tRNA was the negative control. COX protein was determined by Western blot. Values in (A) are the means of three independent experiments. *Significantly different from young mice at P < 0.03. Data adapted from Hayek et al. (1997) .

	Vitamin E decreases in the macrophage PGE2 production of the aged

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

Atherosclerosis has been referred to as an inflammatory process. The dysregulated interaction between blood monocytes/M and endothelium of blood vessels is believed to be an initial step in the process leading to the pathogenesis of atherosclerosis. Evidence from epidemiologic and some clinical intervention trials indicates that vitamin E may reduce the risk of CVD and might potentially be used to prevent CVD. Many mechanistic studies have revealed that vitamin E can modulate various factors that contribute to the progression of atherosclerosis. Of interest to this paper is the ability of vitamin E to regulate M eicosanoid production. Thus, we conducted a study (Wu et al. 1998b) to determine whether M production of PGE₂, especially its increase with age, can be modified by dietary vitamin E supplementation, and if so, to identify its mechanism of action. In this study, we used specific pathogen-free male young (6 mo), and old (24 mo) C57BL/6NIA mice. These mice were fed purified diets containing 30 ppm (adequate level) or 500 ppm vitamin E (RRR--tocopherol acetate) for 30 d. At the end of the feeding period, mice were killed and peritoneal resident M were collected. M were incubated in the presence or absence of LPS for 0, 6, 12, or 24 h at 37°C. PGE₂ produced by M were measured in culture medium by RIA. COX activity of M was determined by measuring PGE₂ that was produced in the presence of exogenously added AA. Results showed that unstimulated M produced very low levels of PGE₂ and there was no significant difference between young and old mice at any of the time points tested. Vitamin E supplementation did not cause a significant change in unstimulated PGE₂ production in either age group. In LPS-stimulated M, as shown in Figure 4A , PGE₂ production by M significantly increased with time in both age groups. M from old mice fed the control diet had significantly higher production of PGE₂ at 12 and 24 h compared with those from young mice fed the control diet. Vitamin E supplementation completely eliminated this age-related increase in PGE₂ production so that there was no significant difference in PGE₂ production between old mice fed 500 ppm vitamin E and young mice fed control or vitamin E-supplemented diets. Vitamin E supplementation, however, did not have a significant effect on PGE₂ production in young mice.

View larger version (33K): [in this window] [in a new window]   Figure 4. Prostaglandin (PG)E2 production (A), cyclooxygenase (COX) activity (B) and COX protein (C) in peritoneal macrophages (M) from young and old C57BL/6NIA mice fed vitamin E. Young and old mice were fed diets containing either 30 or 500 ppm vitamin E for 30 d. M were isolated and incubated in the presence of 5 µg/mL lipopolysaccharide for different lengths of time as indicated. PGE2 in the supernatants was determined by RIA. COX activity was determined by measuring PGE2 production in presence of 30 µmol/L exogenous AA within 10 min. COX protein was determined by Western blot in M from old mice only. Results are means ± SEM, n = 10 (A and B) and n = 4 (C). *Significantly different from young mice at P < 0.05. Data adapted from Wu et al. (1998a) .

	Inhibition of COX by vitamin E is post-translational

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

 
In many cases, the altered COX activity reflects changes in the rate of enzyme synthesis, the rate of mRNA transcription or both. Thus, to clarify further how vitamin E modifies COX activity in old mice, we examined COX protein and mRNA expression. As shown in Figure 4C , LPS-induced COX-2 protein expression was not affected by vitamin E supplementation. Similarly, COX-2 mRNA expression was not influenced by vitamin E (data not shown). Thus, the vitamin E-induced decrease in COX activity of M from old mice is not due to its regulation of COX transcription or translation; rather, it appears that vitamin E exerts its effect post-translationally.

COX activity requires the presence of oxidant hydroperoxides (Hemler and Lands 1980 , Kulmacz and Wang 1995 , Smith et al. 1992 ). The lag phase in attaining maximal COX activity was shortened or eliminated by endogenous or exogenous hydroperoxides, whereas it was delayed by antioxidants (Hemler and Lands 1980 ). Vitamin E is an effective biological antioxidant and chain-breaking free radical scavenger; therefore, it may attenuate COX activity by scavenging the oxidant hydroperoxide necessary for COX activation. The observation that vitamin E inhibits COX activity in old but not young mice further supports this notion because many studies have demonstrated increased formation of lipid peroxides in different tissues of aged animals. Free radical nitric oxide (NO) has been shown to be involved in regulation of COX activity and eicosanoid metabolism. It has been suggested that NO stimulates COX activity via direct stimulation of the enzyme (Salvemini et al. 1995 ). We have reported (Beharka et al. 1997 ) that LPS-stimulated peritoneal M from old mice produced more NO than those from young mice, and dietary supplementation with vitamin E reduced NO production in M from old mice. NO can be further metabolized to peroxynitrite (ONOO) in the presence of superoxide (SO), and ONOO has been shown to increase the activity of COX without affecting its expression. Therefore we hypothesized that decreased NO and thus ONOO formation may mediate the inhibition of COX activity by vitamin E. To test this hypothesis, we conducted a study (Beharka et al. 2000 ) in which young (6 mo) and old (24 mo) mice were fed 30 or 500 ppm vitamin E for 30 d. The results confirmed the previous findings that M from old mice produced more NO than those from young mice, and this age-associated increase of NO was reduced by vitamin E supplementation. However, SO levels were not affected by age or vitamin E supplementation. Addition of NO donor to the cell culture to increase NO levels did not change PGE₂ production and COX activity in either young or old mice. However, when NO donor was added in the presence of SO to elevate ONOO levels in the culture, COX activity was increased in the M from old mice fed 500 ppm but not 30 ppm vitamin E. On the other hand when NO and SO inhibitors were added to M from old mice fed 30 ppm vitamin E to block the generation of ONOO, COX activity was reduced significantly. These results suggest that vitamin E reduces COX activity in old M by decreasing NO production, which leads to lower production of ONOO in M from old mice.

	In vitro supplementation with various tocopherol homologues differentially affects COX activity

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

 
A majority of studies on vitamin E, including those mentioned above, have used -tocopherol (-T). However, in recent years, interest in determining the biological effects of non--tocopherols has increased. It is generally agreed that the relative antioxidant activity of tocopherols is in the order > ß > > (Burton and Ingold 1981 , Kamal-Eldin and Appelqvist 1996 ), but recent studies have provided evidence that in some in vitro systems, other tocopherols might be more effective antioxidants than -tocopherol. For example, -T was shown to inhibit peroxynitrite-induced lipid peroxidation more effectively than -T (Christen et al. 1997 ). It has been suggested that the varied biological activity of tocopherols is explained only in part by their antioxidant activity (Azzi et al. 1993 , Kasparek 1980 ). -T has been studied extensively and is well documented for its beneficial effect in several bodily systems, in particular, the cardiovascular and immune systems (Diaz et al. 1997 , Meydani 1995 , Meydani and Beharka 1998 , Weber et al. 1997 ). In contrast, the other forms of tocopherols, especially ß- and -T have received little attention for their biological effects other than their antioxidant property. In fact, non--tocopherols are abundant in certain plant oils and thus may contribute to the total tocopherol bioactivity in food. Although the concentrations of these non--tocopherols in tissues and body fluids are much lower and they are less effective as biological antioxidants compared with -T, their ability to modulate various other aspects of cell function has not been studied. We have shown that dietary or in vitro supplementation with -T inhibited PGE₂ production and COX activity in M from old mice. We, therefore, conducted another study (Wu et al. 2000 ) to compare the effect of in vitro supplementation with all four natural tocopherols on the function of immune cells in old mice, including PGE₂ production and COX activity. In this study, peritoneal M were obtained from 26-mo-old male C57BL mice. After 4 h of preincubation with graded levels of each of the four tocopherols, M were stimulated with LPS for 24 h. As shown in Figure 5 and Table 2 , accumulated PGE₂ production using the endogenous substrate, AA, was inhibited by all concentrations of -T tested; there was no difference among the doses tested. ß-T did not have an effect on accumulated PGE₂ production, whereas - and -T inhibited PGE₂ production in a dose-dependent manner. However, COX activity, as determined by the synthesis of PGE₂ from exogenous AA, was inhibited by all four tocopherols including ß-T. These results indicate that non--T homologues can also inhibit COX activity, and this effect does not seem to depend solely on their antioxidant capacity. The inconsistent effect of ß-T on accumulated PGE₂ and COX activity suggests that some mechanism other than COX, such as modulation of phospholipase A₂, might also be involved in determining the net effect of various tocopherol isomers on PGE₂ production (Table 3) .

View larger version (39K): [in this window] [in a new window]   Figure 5. Effect of tocopherol isomers on prostaglandin (PG)E2 production and cyclooxygenase (COX) activity of mouse peritoneal macrophages (M). M were isolated from 26-mo-old C57BL/6NcrlBR mice and were incubated with the tocopherols at specified concentrations for 4 h. M were then stimulated with 5 µg/mL lipopolysaccharide for 24 h. PGE2 in the supernatants was determined by RIA. COX activity was determined by measuring PGE2 production in presence of 30 µmol/L exogenous arachidonic acid within 10 min. Results are means ± SEM, n = 5. Significantly different from control at *P < 0.01 or #P < 0.05. Data adapted from Wu et al. (2000) .

	SUMMARY

TOP ABSTRACT INTRODUCTION Upregulation of PGE2 production... Vitamin E decreases in... Inhibition of COX by... In vitro supplementation with... SUMMARY REFERENCES

	ACKNOWLEDGMENTS

 
The authors would like to thank Kate J. Claycombe for her help with the graphical presentation of the data.

	FOOTNOTES

 
¹ Presented as part of the symposium, Molecular Mechanisms of Protective Effects of Vitamin E in Atherosclerosis, given at Experimental Biology 2000, April 16, 2000 in San Diego, CA. This symposium was sponsored by the American Society for Nutritional Sciences and was supported by an educational grant from Archer Daniels Midland Company and BASF corporation. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors for the supplement publication were Mohsen Meydani, Tufts School of Nutrition Science and Policy and Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA and Maret G. Traber, Linus Pauling Institute, Oregon State University, Corvallis, OR and University of California, Davis, School of Medicine, Sacramento, CA.

² Supported by the U.S. Department of Agriculture, under agreement no. 58–1950-9–001, and by NIA grant #2 RO1 AG 09140–07. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U.S. Department of Agriculture.

⁴ Abbreviations: AA, arachidonic acid; -T, -tocopherol; CMV, cytomegalovirus; ConA, concanavalin A; COX, cyclooxygenase; CVD, cardiovascular disease; HETE, hydroxyeicosatetraenoic acid; iNOS, inducible nitric oxide synthetase; LPS, lipopolysaccharide; LT, leukotriene; M, macrophages; ONOO, peroxynitrite; PG, prostaglandin; PGH₂, PG endoperoxide; SO, superoxide; TX, thromboxane.

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