Modulation of cytochrome-derived epoxyeicosatrienoic acids pathway: a promising pharmacological approach to prevent endothelial dysfunction in cardiovascular diseases?

Abstract

Progress in methods of investigating endothelial function in humans has led to the demonstration that endothelial dysfunction is an early process involved in the pathophysiology of cardiovascular diseases, and represents a new independent therapeutic target that may help to improve patient health. The administration of antioxidant, anti-hypertensive, lipid lowering or antidiabetic agents appear insufficient to fully restore the normal functions of the vascular endothelium and specific therapeutic strategies are still lacking. In this context, one emerging promising pharmacological approach to prevent endothelial dysfunction is to restore epoxyeicosatrienoic acids (EETs) pathway. EETs are eicosanoids synthesized by endothelial cytochrome epoxygenases that contribute to the regulation of endothelium-dependent dilatation, vascular inflammation, cell proliferation, angiogenesis and hemostasis. Moreover, it has been shown in vivo in humans that EETs act as endothelium-derived hyperpolarizing factors to regulate the vascular tone in both resistance and conduit arteries. In various cardiovascular disorders such as arterial hypertension, a decrease in EETs availability, due to an increased degradation by soluble epoxide hydrolase (sEH), is a deleterious mechanism that contributes to endothelial dysfunction and promotes cardiovascular inflammation and remodeling. Subsequently, the use of sEH inhibitors, which have been shown to decrease blood pressure, limit ischemic injury and prevent hypertrophy in various animal models, appears to be an attractive opportunity to restore endothelial function. Future research will be necessary to demonstrate that sEH inhibitors can prevent endothelial dysfunction in human arteries, which may help to prevent the development of cardiovascular complications and improve cardiovascular prognosis in patients.