Targeting Epoxides for Organ Damage in Hypertension

Abstract

Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid and EETs have a number of beneficial cardiovascular actions. This has led to the concept that EETs and its metabolic pathway can be therapeutically targeted for hypertension and other cardiovascular diseases. One approach has been to prevent the conversion of EETs to their inactive diols by inhibiting the soluble epoxide hydrolase (sEH) enzyme. Inhibition of sEH has been demonstrated to decrease blood pressure in certain experimental models of hypertension, decrease inflammation, and protect organs from damage associated with hypertension and other cardiovascular diseases. The development of sEH inhibitors has reached the point where they are being evaluated in humans. A second therapeutic approach has been to develop EET agonists. EET agonists have been essential for determining the structure function relationship for EETs and determining cell-signaling mechanisms by which EETs exert their cardiovascular actions. More recently, EET agonists have been administered chronically to experimental animal models of hypertension and metabolic syndrome and have been demonstrated to decrease blood pressure, improve insulin signaling, and improve vascular function. These experimental findings provide evidence for sEH inhibitors and EET agonists as a therapeutic approach for cardiovascular diseases, hypertension, and the associated end organ damage.

Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage

“…EETs not only are involved in regulating vascular tone and antagonizing the vasoconstrictor actions of AngII but also directly influence tubular transport of sodium (13). In our study, the level of sEH was elevated along with increased EMT and inflammation in culture RPTECs, whose effects were mimicked with adenovirus-mediated sEH overexpression and attenuated by an sEH inhibitor in vitro and in ADR-induced nephropathy mice.…”

“…Genetic deletion of sEH, as well as pharmacological inhibition, increases plasma EET levels and potentiates their effects (22,23); thus sEH inhibition has antihypertensive and anti-inflammatory effects. Indeed, sEH inhibition may reduce hypertension, myocardial infarct size, cerebral infarction, vascular remodeling and atherosclerosis, and even tobacco smoke-induced airway inflammation (5,13,30).…”

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…Effects on basal blood pressure aside, sEH inhibitors are very effective in the treatment of hypertension associated with activation of the renin-angiotensin system (for review, see Imig, 2010). This fact is explained by the finding that angiotensin II is a potent inducer of sEH expression the rat vasculature (Ai et al, 2007) as well as the rat heart (Ai et al, 2009).…”

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

“…Beside vasoactive properties, EETs also display potent anti-inflammatory, antiplatelet and antithrombotic activities [22]. EETs increase the rate of growth in endothelial cells, stimulate angiogenesis and inhibit the proliferation of human VSMCs.…”