Inhibition of soluble epoxide hydrolase attenuated atherosclerosis, abdominal aortic aneurysm formation, and dyslipidemia
| Autor: | Upasana Mehra, Le-Ning Zhang, Jon Vincelette, Yi-Xin Jim Wang, Ying Cheng, Dawn Chen, Sampath-Kumar Anandan, Richard D. Gless, Heather K. Webb |
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| Rok vydání: | 2009 |
| Předmět: |
Epoxide hydrolase 2
Male medicine.medical_specialty Apolipoprotein B Administration Oral Biological Availability Down-Regulation Vascular Cell Adhesion Molecule-1 Pharmacology Lesion Mice Apolipoproteins E Downregulation and upregulation Interleukin-1alpha medicine Animals Arterial wall Enzyme Inhibitors Ligation Dyslipidemias Epoxide Hydrolases Mice Knockout biology business.industry Interleukin-6 Angiotensin II Interleukin-8 medicine.disease Atherosclerosis Intercellular Adhesion Molecule-1 Abdominal aortic aneurysm Surgery Disease Models Animal Carotid Arteries Cholesterol biology.protein medicine.symptom Inflammation Mediators Cardiology and Cardiovascular Medicine business Dyslipidemia Aortic Aneurysm Abdominal |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 29(9) |
| ISSN: | 1524-4636 |
| Popis: | Objective— Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. Methods and Results— Six-month-old apolipoprotein E–deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1α, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. Conclusions— The present data demonstrate that treatment with an s-EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant downregulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects. |
| Databáze: | OpenAIRE |
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