Abstract
To determine whether sEH inhibitors influence atherosclerotic lesion formation, we used an established murine model of accelerated atherogenesis, ApoE knockout (-/-) mice. The sEH inhibitor, 1-adamantan-3-(5-(2-(2-ethylethoxy) ethoxy)pentyl)urea (AEPU) was delivered in drinking water. All animals were fed an atherogenic diet while simultaneously infused with angiotensin II by osmotic minipump to induce atherosclerosis. In AEPU-treated animals, there was a 53% reduction in atherosclerotic lesions in the descending aortae as compared to control aortae. AEPU and its major metabolites were detected in the plasma of animals which received it. As expected from the inhibition of sEH, a significant increase in linoleic and arachidonic acid epoxides, as well as an increase in individual 11,12-EET/DHET and 14,15-EET/DHET ratios, were observed. The reduction in atherosclerotic lesion area was inversely correlated with 11,12- and 14,15- EET/DHET ratios, suggesting that the reduction corresponds to the inhibition of sEH. Our data suggest that orally-available sEH inhibitors may be useful in the treatment of patients with atherosclerotic cardiovascular disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 314-323 |
| Number of pages | 10 |
| Journal | Journal of Cardiovascular Pharmacology |
| Volume | 52 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2008 |
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Keywords
- 1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl) urea
- Apo E knockout mice
- Atherosclerosis
- Epoxyeicosatrienoic acid
- Soluble epoxide hydrolase
ASJC Scopus subject areas
- Pharmacology
- Cardiology and Cardiovascular Medicine
Cite this
Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein E-knockout mouse model. / Ulu, Arzu; Davis, Benjamin B.; Tsai, Hsing Ju; Kim, In Hae; Morisseau, Christophe; Inceoglu, Bora; Fiehn, Oliver; Hammock, Bruce D.; Weiss, Robert H.
In: Journal of Cardiovascular Pharmacology, Vol. 52, No. 4, 10.2008, p. 314-323.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein E-knockout mouse model
AU - Ulu, Arzu
AU - Davis, Benjamin B.
AU - Tsai, Hsing Ju
AU - Kim, In Hae
AU - Morisseau, Christophe
AU - Inceoglu, Bora
AU - Fiehn, Oliver
AU - Hammock, Bruce D.
AU - Weiss, Robert H
PY - 2008/10
Y1 - 2008/10
N2 - To determine whether sEH inhibitors influence atherosclerotic lesion formation, we used an established murine model of accelerated atherogenesis, ApoE knockout (-/-) mice. The sEH inhibitor, 1-adamantan-3-(5-(2-(2-ethylethoxy) ethoxy)pentyl)urea (AEPU) was delivered in drinking water. All animals were fed an atherogenic diet while simultaneously infused with angiotensin II by osmotic minipump to induce atherosclerosis. In AEPU-treated animals, there was a 53% reduction in atherosclerotic lesions in the descending aortae as compared to control aortae. AEPU and its major metabolites were detected in the plasma of animals which received it. As expected from the inhibition of sEH, a significant increase in linoleic and arachidonic acid epoxides, as well as an increase in individual 11,12-EET/DHET and 14,15-EET/DHET ratios, were observed. The reduction in atherosclerotic lesion area was inversely correlated with 11,12- and 14,15- EET/DHET ratios, suggesting that the reduction corresponds to the inhibition of sEH. Our data suggest that orally-available sEH inhibitors may be useful in the treatment of patients with atherosclerotic cardiovascular disease.
AB - To determine whether sEH inhibitors influence atherosclerotic lesion formation, we used an established murine model of accelerated atherogenesis, ApoE knockout (-/-) mice. The sEH inhibitor, 1-adamantan-3-(5-(2-(2-ethylethoxy) ethoxy)pentyl)urea (AEPU) was delivered in drinking water. All animals were fed an atherogenic diet while simultaneously infused with angiotensin II by osmotic minipump to induce atherosclerosis. In AEPU-treated animals, there was a 53% reduction in atherosclerotic lesions in the descending aortae as compared to control aortae. AEPU and its major metabolites were detected in the plasma of animals which received it. As expected from the inhibition of sEH, a significant increase in linoleic and arachidonic acid epoxides, as well as an increase in individual 11,12-EET/DHET and 14,15-EET/DHET ratios, were observed. The reduction in atherosclerotic lesion area was inversely correlated with 11,12- and 14,15- EET/DHET ratios, suggesting that the reduction corresponds to the inhibition of sEH. Our data suggest that orally-available sEH inhibitors may be useful in the treatment of patients with atherosclerotic cardiovascular disease.
KW - 1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl) urea
KW - Apo E knockout mice
KW - Atherosclerosis
KW - Epoxyeicosatrienoic acid
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=58149350130&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149350130&partnerID=8YFLogxK
U2 - 10.1097/FJC.0b013e318185fa3c
DO - 10.1097/FJC.0b013e318185fa3c
M3 - Article
VL - 52
SP - 314
EP - 323
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
SN - 0160-2446
IS - 4
ER -