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Vitamin E and macrophage cyclooxygenase regulation in the aged
1Nutritional Immunology Laboratory, Jean Mayer Human Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Insights
Aging increases prostaglandin E(2) (PGE(2)) and cyclooxygenase-2 (COX-2) activity, contributing to cardiovascular disease risk. Vitamin E reduces PGE(2) via post-translational COX inhibition, potentially lowering CVD risk.
Area of Science:
- Biomedical Science
- Cardiovascular Research
- Aging Research
Background:
- Aging is linked to increased cardiovascular disease (CVD), with atherosclerosis playing a key role.
- Prostaglandin E(2) (PGE(2)) and thromboxane A(2) (TXA(2)), products of arachidonic acid metabolism, are implicated in atherosclerosis development.
- Aged individuals exhibit higher PGE(2) production due to increased cyclooxygenase (COX) activity, specifically COX-2.
Purpose of the Study:
- To investigate the role of vitamin E in modulating PGE(2) production and COX activity in aged mice.
- To elucidate the mechanism by which vitamin E influences COX activity, particularly its potential post-translational effects.
- To explore the contribution of vitamin E-mediated COX inhibition to the reduction of CVD risk.
Main Methods:
- Comparison of PGE(2) production and COX activity between young and aged mice.
- Administration of vitamin E to aged mice to assess its effects on PGE(2) levels and COX activity.
- Analysis of COX mRNA and protein expression following vitamin E treatment.
- Investigation of peroxynitrite formation as a potential mediator of vitamin E's effect on COX activity.
Main Results:
- Aged mice show elevated PGE(2) production primarily due to increased COX activity, specifically COX-2 expression.
- Vitamin E administration to aged mice decreased PGE(2) production by inhibiting COX activity.
- Vitamin E did not alter COX mRNA or protein levels, suggesting post-translational regulation.
- Vitamin E reduced COX activity by decreasing peroxynitrite formation, a COX-2 activator.
Conclusions:
- Vitamin E effectively reduces PGE(2) production in aged mice through post-translational inhibition of COX activity.
- The mechanism involves the reduction of peroxynitrite, impacting COX-2 activation.
- Vitamin E's ability to inhibit COX activity may contribute to its protective effects against cardiovascular disease.
Abstract:
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) E(2) and thromboxane (TX) A(2), play an important role in the development of atherosclerosis. We showed previously that the aged have higher PGE(2) production compared with their young counterparts. This age-associated increase in PGE(2) 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 PGE(2) production and risk of CVD. In aged mice, we showed that a vitamin E-induced decrease in PGE(2) 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.