Abstract
Inflammation is a key element in many cardiovascular diseases. Both estrogen loss, caused by menopause, and aging have inflammatory consequences. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory molecules synthesized by various cytochrome P450 (Cyp) enzymes from arachidonic acid. EETs are in the third (Cytochrome P450) pathway of arachindonic acid metabolism, others being cyclooxygenases and lipoxygenases. We hypothesized that aging and estrogen loss would reduce levels of anti-inflammatory EETs. Adult (6 mo) and aged (22 mo) ovariectomized rats with (OP) and without (Ovx) 17-∃-estradiol replacement were used in this study. Mass spectrometry was used to measure levels of EETs and their metabolites, dihydroxyeicosatrienoic acids (DHETs). Levels of Cyp2C2, Cyp2C6, and Cyp2J2, the principal Cyps responsible for EETs synthesis, as well as soluble epoxide hydrolase (sEH), which metabolizes EETS to DHETs, were determined via western blot. Overall Cyp levels decreased with age, though Cyp2C6 increased in the liver. sEH was increased in the kidney with estrogen replacement. Despite protein changes, no differences were measured in plasma or aortic tissue levels of EETs. However, plasma 14,15 DHET was increased in aged Ovx, and 5,6 DHET in adult OP. In conclusion neither aging nor estrogen loss decreased the anti-inflammatory EETs in the cardiovascular system.
Highlights
Menopause is characterized by dramatically decreased estrogen levels and a marked acceleration of atherosclerosis and heart disease in women [1]
Aging led to a decrease in cytochrome P450 (Cyp) protein levels, though an increase was seen in liver Cyp 2C6 level. soluble epoxide hydrolase (sEH) levels, by contrast, varied only in the kidney, based on estrogen status, with both OP groups showing increased amounts of sEH
Epoxyeicosatrienoic acids (EETs) Synthesis EETs are formed by the metabolism of arachidonic acid by cytochrome P450 epoxygenases
Summary
Menopause is characterized by dramatically decreased estrogen levels and a marked acceleration of atherosclerosis and heart disease in women [1]. Nonrandomized studies had supported that HRT was cardio-protective for women post-menopause, the randomized, double-blinded clinical trials showed an increase in cardiovascular events, during the first year of treatment. Further analysis of these results led to the timing hypothesis [6], that a long delay between menopause and HRT was a factor in the increased cardiovascular disease in the trials. Recent work from our lab indicates that delayed estrogen administration leads to an increase in inflammatory gene expression [7], signifying that inflammation plays a role in the deleterious effects seen with late estrogen administration in the clinical trials. Because inflammatory changes have been definitively associated with the development of atherosclerosis [8,9], the identification of antioxidant and antiinflammatory pathways and molecules has become paramount
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