Epoxyeicosatrienoic acid analogs and vascular function

Abstract

Arachidonic acid metabolites, eicosanoids, are key contributors to vascular function and improper eicosanoid regulation contributes to the progression of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by epoxygenase enzymes to four regioisomers, 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. These EETs have interesting beneficial effects like vasodilation, anti-inflammation, and anti-platelet aggregation that could combat cardiovascular diseases. There is mounting evidence that each regioisomeric EET may have unique vascular effects and that the contribution of individual EETs to vascular function differs from organ to organ. Over the past decade EET analogs and antagonists have been synthesized to determine EET structure function relationships and define the contribution of each regioisomeric EET. A number of studies have demonstrated that EET analogs induce vasodilation, lower blood pressure and decrease inflammation. EET antagonists have also been used to demonstrate that endogenous EETs contribute importantly to cardiovascular function. This review will discuss EET synthesis, regulation and physiological roles in the cardiovascular system. Next we will focus on the development of EET analogs and what has been learned about their contribution to vascular function. Finally, the development of EET antagonists and how these have been utilized to determine the cardiovascular actions of endogenous epoxides will be discussed. Overall, this review will highlight the important knowledge garnered by the development of EET analogs and their possible value in the treatment of cardiovascular diseases.

Figure 1

Epoxides are generated from arachidonic acid. Arachidonic acid is converted to epoxyeicosatrienoic acid (EET) by cytochrome P450 (CYP) epoxygenase. EETs primary metabolic fate is conversion to dihydroxyeicosatrienoic acids (DHETs) by the soluble epoxide hydrolase (sEH) enzyme.

Figure 2

Epoxyeicosatrienoic acid (EET) activate vascular (panel A) and anti-inflammatory (panel B) cell signaling mechanisms. Panel A: Endothelial cell proliferation and angiogensis involves activation of p38 mitogen-activated protein (MAPK), phosphatidylinositol 3-kinase (PI3-K), kinase Akt, forkhead factors (FOXO) and cyclin D. Vasorelaxation involves activation G protein (Gαs), adenylyl cyclase (AC) generation of cAMP, protein kinase A (PKA) and opening of large-conductance calcium-activated potassium channels (BK_Ca). Panel B: EET anti-inflammatory action involves inhibition of tumor necrosis factor-α(TNF-α) activation of the IK kinase (IKK). IKK induces phosphorylation of the NFκB inhibitor IκB that results in ubiquitination and degradation IκB. NFκB dimmers (RelA/p50) translocate to the nucleus and activate pro-inflammatory genes such as cyclooxygenase-2 (COX-2).

Figure 3

Chemical structures of 14,15-epoxyeicosatrienoic acid (EET) analogs with alterations in the epoxide group (A-B), the position of double bonds (C-E), carbon chain length (F-H), carboxyl group (I-J), and combinational changes (K). A structure activity domain map for 14,15-EET (L) includes 5 regions: 1.) ionic attraction at carbon-1; 2.) lipophilic region; 3.) 8,9-olefin double bond; 4.) 14,15-epoxide; 5.) terminal lipophilic pocket.

Figure 4

EET analogs have anti-hypertensive actions. Decreased blood pressure in spontaneously hypertensive rats (SHR) treated for one week with an 11-nonyloxy-undec-8(Z)-eonic acid (6 mg/kg/d i.p.).