Novel treatments for atherosclerosis with inhibitors of soluble epoxide hydrolase

The purpose of this study is to investigate the potential use of sEH inhibitors as a treatment to reduce or prevent atherosclerosis. Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. Consistently elevated blood pressure can lead to atherosclerosis, a process that is at least in part due to aberrant proliferation of arterial smooth muscle cells and in part due to a generalized inflammatory condition. Thus, novel medications that result in systemic anti-hypertensive, anti-inflammatory effects and attenuation of vascular smooth muscle (VSM) cell proliferation would provide a three-pronged attack on the atherosclerotic process.; My work has focused on the affect of sEH inhibitors on VSM cell proliferation and is based on previous work demonstrating their anti-hypertensive and anti-inflammatory properties. In my studies, I find that (1) 1-cyclohexyl-3-dodecylurea (CDU) attenuates proliferation of HVSM cells with no apparent toxicity and decreases cyclin D1 levels independent of changes in MAP/ERK phosphorylation, (2) CDU attenuates proliferation in HVSM cells independently of it's actions on sEH. Other findings include: four new inhibitors of sEH do not effect proliferation, EETs do not affect proliferation in HVSM cells, and lastly cultured HVSM cells lack functional sEH. (3) Lastly in a collaborative work we determined that soluble epoxide hydrolase is expressed in renal arteries of varying diameter and is localized mostly in the smooth muscle layers of the arterial wall. Furthermore, we found no obvious differences in sEH expression between normal and diseased human kidney tissue in the samples examine.; The work describe herein is an important step to developing sEH inhibitors as anti-atherosclerosic drugs. It is the first demonstration that a sEH inhibitor can attenuate human VSM cell proliferation. This is significant as VSM cell proliferation is a key component in the development atherosclerosis. Several key components of the underling cellular mechanism by which this sEH inhibitor reduces proliferation are revealed. Furthermore, evidence that sEH is expressed in the VSM cells of human renal arterioles that play a key role in blood pressure regulation provides a beginning step to the eventual transition from studying sEH in animal models to clinical investigation. Additionally, this study helps to define the limitations of cell culture models using sEH inhibitors that will help to guide future investigation into eicosanoid biology. Lastly, results from this work have laid the foundation for the ongoing research testing the efficacy of these compounds in animal models of atherosclerosis.