Epoxides and soluble epoxide hydrolase in cardiovascular physiology

Abstract

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that importantly contribute to vascular and cardiac physiology. The contribution of EETs to vascular and cardiac function is further influenced by soluble epoxide hydrolase (sEH) that degrades EETs to diols. Vascular actions of EETs include dilation and angiogenesis. EETs also decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis. Myocyte contraction and increased coronary blood flow are the two primary EET actions in the heart. EET cell signaling mechanisms are tissue and organ specific and provide significant evidence for the existence of EET receptors. Additionally, pharmacological and genetic manipulations of EETs and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases. Given the impact of EETs to cardiovascular physiology, there is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases.

Figure 1

Cytochrome P-450 epoxygenase metabolic pathway. A: epoxides are generated from arachidonic acid. Arachidonic acid is converted to epoxyeicosatrienoic acid (EET) by cytochrome P-450 (CYP) epoxygenase. EETs primary metabolic fate is conversion to dihydroxyeicosatrienoic acids (DHETs) by the soluble epoxide hydrolase (sEH) enzyme. B: CYP epoxygenases generate cis-epoxides, whereas cis- and trans-epoxides exist in plasma (22, 151, 263). The enzymes that form trans-EETs remain unknown but could occur through radical-driven reactions (148, 151).

Figure 2

EETs vasodilation is mediated by multiple mechanisms. A summary of vascular cell signaling mechanisms utilized by regioisomeric EETs in various organs is given. A: EETs generated by endothelial cells activate TRPV4 channels on vascular smooth muscle cells. Calcium influx through TRPV4 channels causes Ca²⁺ sparks from the endoplasmic reticulum. Ca²⁺ sparks activate large-conductance Ca²⁺-activated K⁺ channels (BK_Ca) resulting in K⁺ efflux from the smooth muscle cell and membrane hyperpolarization. B: EETs activate endothelial cell transient receptor potential (TRP) channels resulting in Ca²⁺ Influx. An increase in endothelial cell Ca²⁺ activates small-conductance (SK_Ca) and intermediate-conductance (IK_Ca) K⁺ channels to cause membrane hyperpolarization. Endothelial membrane hyperpolarization spreads to the vascular smooth muscle cell via gap junctions. C: EETs released by endothelial cells activate an unidentified receptor stimulating cAMP production via activation of adenylyl cyclase by the guanine nucleotide protein Gα_s. Subsequent protein kinase A (PKA) activation by cAMP results in activation of BK_Ca and K_ATP, K⁺ efflux, and smooth muscle cell hyperpolarization.

Figure 3

EETs intracellular signaling pathways resulting in angiogenesis. An overview of intracellular pathways that have been demonstrated to be activated by regioisomeric EETs to promote angiogenesis is given. Mitogen-activated protein kinase (MAPK) can increase nuclear cyclin D1 generation. Sphingosine kinase-1 (SK-1) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways can activate transcription factors and the generation of cell cycle modulators. Protein kinase A (PKA) acting via the cAMP/PKA response element binding protein (CREBP) results in COX-2 production that influences angiogenesis, cell migration, and fibrinolysis.

Figure 4

EETs cardioprotection and protection from ischemic injury. EETs have been postulated to directly activate sarcolemmal K_ATP, mitochondrial K_ATP (mitoK_ATP), and mitochondrial K_Ca (mitoK_Ca) to limit the loss of mitochondrial membrane potential (Δψ_m) to slow opening of the mitochondrial permeability transition pore (mPTP) resulting in decreased apoptosis (157). Other intracellular signaling mechanisms include PI3K/Akt inhibition of GSK3β, MAPK- and PKA/CRBP-mediated inhibition of JNK activation, and STAT-3 tyrosine phosphorylation-mediated nuclear translocation.