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. 2013 Aug 13;8(8):e70719.
doi: 10.1371/journal.pone.0070719. eCollection 2013.

Aging, estrogen loss and epoxyeicosatrienoic acids (EETs)

Alison R Lee  1 , Angela S Pechenino, Hua Dong, Bruce D Hammock, Anne A Knowlton
Affiliations

Aging, estrogen loss and epoxyeicosatrienoic acids (EETs)

Alison R Lee et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Diagram summarizes key steps in EETs synthesis and metabolism.
Figure 2
Figure 2. Plasma levels of EETs and DHETs from MS analysis.
A: EETs levels. B: DHETs levels. Adult Ovx- white bars, Adult OP- white bars with pattern, Aged Ovx- grey bars, Aged OP- grey bars with pattern. # P<0.05 compared with Adult OP, * P<0.001 compared with all. n = 6–8/group for EETs; n = 5–8/group for DHETs, except 5,6 DHET where n = 3–4/group.
Figure 3
Figure 3. Western blot analysis of liver and kidney EETs related genes, normalized to GAPDH.
A representative Western blot showing bands from each of the 4 groups in the order they are given on the graph plus a representative GAPDH blot are shown for each graph. A: Cyp2C2, Cyp2J2 and Cyp2C6 in liver. B: sEH in liver. C: Cyp2C2, Cyp2J2 and Cyp2C6 in kidney. D: sEH in kidney. # P<0.05 compared with Adult OP, * P<0.05 compared with Adult Ovx; n = 9–11/group.
Figure 4
Figure 4. Western blot analysis of aorta EETs related genes, normalized to GAPDH.
A representative Western blot showing bands from each of the 4 groups in the order they are given on the graph plus a representative GAPDH blot are shown for each graph. A: Cyp2C2, Cyp2J2 and Cyp2C6 in aorta. B: sEH in aorta. n = 6–9/group.
Figure 5
Figure 5. Western blot analysis of left ventricle EETs related genes, normalized to GAPDH.
A representative Western blot showing bands from each of the 4 groups in the order they are given on the graph plus a representative GAPDH blot are shown for each graph. A: Cyp2C2, Cyp2J2 and Cyp2C6 in LV. B: sEH in LV. # P<0.05 compared with Adult OP, * P<0.05 compared with Adult Ovx; n = 9–11/group.
Figure 6
Figure 6. Aortic levels of EETs from MS analysis.
Adult Ovx- white bars, Adult OP- white bars with pattern, Aged Ovx- grey bars, Aged OP- grey bars with pattern. n = 3–5/group.
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