Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and it is well known that end-stage renal disease (ESRD) is a profound consequence of the progression of CVD. Present treatments only slow CVD progression to ESRD, and it is imperative that new therapeutic strategies are developed to prevent the incidence of ESRD. Because epoxyeicosatrienoic acids (EETs) have been shown to elicit reno-protective effects in hypertensive animal models, the current review will focus on addressing the reno-protective mechanisms of EETs in CVD. The cytochrome P-450 epoxygenase catalyzes the oxidation of arachidonic acid to EETs. EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs) with vasodilatory, anti-inflammatory, antihypertensive, and antiplatelet aggregation properties. EETs also have profound effects on vascular migration and proliferation and promote angiogenesis. The progression of CVD has been linked to decreased EETs levels, leading to the concept that EETs should be therapeutically targeted to prevent end-organ damage associated with CVD. However, EETs are quickly degraded by the enzyme soluble epoxide hydrolase (sEH) to their less active diols, dihydroxyeicosatrienoic acids (DHETs). As such, one way to increase EETs level is to inhibit their degradation to DHETs by using sEH inhibitors. Inhibition of sEH has been shown to effectively reduce blood pressure and organ damage in experimental models of CVD. Another approach to target EETs is to develop EET analogs with improved solubility and resistance to auto-oxidation and metabolism by sEH. For example, stable ether EET analogs dilate afferent arterioles and lower blood pressure in hypertensive rodent animal models. EET agonists also improve insulin signaling and vascular function in animal models of metabolic syndrome.

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

“…There is a phenomenal amount of data demonstrating the importance of the P450/sEH axis in renal physiology and the ability of EETs to increase renal blood flow and the glomerular filtration rate as well as to decrease renal vascular resistance, as reviewed extensively elsewhere Elmarakby, 2012;Capdevila and Wang, 2013). In the kidney, EETs and 20-HETE are also produced in the proximal tubule, the thick ascending loop of Henle, and the cortical collecting duct, where they modulate ion transport.…”

Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

“…The pathophysiology of diabetic renal injury is multifactorial; however, inflammation and oxidative stress are the main keys in the pathogenesis of the disease [5]. Because induction of diabetes with streptozotocin increases proteinuria and oxidative stress without a change in arterial pressure in Sprague-Dawley rats [6], superimposing streptozotocininduced diabetes on hypertension background could provide a better clinically relevant picture to signs and symptoms of diabetic renal injury.…”

“…Accordingly, we have recently demonstrated that diabetic SHR (spontaneously hypertensive rats) are an www.clinsci.org 349 Clinical Science www.clinsci.org excellent experimental model of diabetic renal injury, where diabetes coexists with hypertension and together exacerbate the progression of renal inflammation and injury similar to the clinical manifestations of the disease [7]. The CYP (cytochrome P450) mono-oxygense pathway catalyses the oxidation of arachidonic acid at any of the four double bonds to four regioisomeric EETs (epoxyeicosatrienoic acids) (5,8,11,(12)(13)(14) by the CYP epoxygenase [5,8]. EETs are EDHFs (endothelium-derived hyperpolarizing factors) with anti-hypertensive and anti-inflammatory properties; however, conversion of EET epoxides into their corresponding diols (DHETs) by sEH (soluble epoxide hydrolase) enzyme limits EETs availability and decreases their potential use to combat cardiovascular disease [5,8].…”

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases

“…Over the past several decades, research has shown that EETs exhibit cardiovascular effects and the cellular signaling mechanisms of EETs have been comprehensively reviewed elsewhere (4,6,(8)(9)(10). There is evidence that EETs interact with G protein-coupled receptors to activate intracellular signaling cascades (11)(12)(13); however, an EET receptor has 1 Supported by grants from the National Natural Science Foundation of China (81100085, 81471021, 91439203, and 31130031).…”