Lipoxygenases in ECs

Enzymology of Lipoxygenases

Lipoxygenases (LOX) are nonheme iron-containing enzymes that catalyze arachidonate or linoleate oxidation to form a series of lipid hydroperoxides. In mammalian cells, several isoforms are known, named by their position of oxygen insertion into arachidonate. Lipoxygenases contain a single nonheme iron that alternates between Fe2+ and Fe3+ during catalysis. Resting enzyme predominantly exists as the reduced form, requiring oxidation by hydroperoxides before dioxygenation can occur.

Vascular and Endothelial Expression of LOX Isoforms

LOX enzymes are predominantly expressed by leukocytes (5- and 15-LOX in humans, rabbits, 12/15-LOX in mice, rats, pigs) and platelets (12-LOX). Under basal conditions, ECs do not appear to express significant LOX protein. However, increased protein expression of 5-LOX has been reported in pulmonary artery ECs of patients with primary pulmonary hypertension, in hypoxic rats, and in antigen-

Figure 3 Effects of PGHS products on endothelial cell function. A series of PGHS metabolites have potent biological effects on endothelial cell function. PPAR, peroxisomal proliferator activating receptor; HO, heme oxygenase; VEGF, vascular endothelial growth factor; 15S-PGJ2, 15-deoxy-S (12,14)-prostaglandin J2; PAI-1, plasminogen activator inhibitor type-1. (see color insert)

Figure 3 Effects of PGHS products on endothelial cell function. A series of PGHS metabolites have potent biological effects on endothelial cell function. PPAR, peroxisomal proliferator activating receptor; HO, heme oxygenase; VEGF, vascular endothelial growth factor; 15S-PGJ2, 15-deoxy-S (12,14)-prostaglandin J2; PAI-1, plasminogen activator inhibitor type-1. (see color insert)

challenged mice. This suggests 5-LOX may be upregulated in inflammatory-activated endothelium, although the mechanisms involved are unknown. Finally, although functional 5-LOX protein is not expressed in ECs, leukotrienes can be generated by HUVECs and pig aortic ECs following intercellular transfer of LOX products from associated granulocytes. It is unknown whether similar generation of leukotrienes can occur in microvascular ECs following granulocyte transfer of precursors.

Regulation of EC Function by LOX Products

LOX products stimulate a variety of EC functions. In particular an important role for platelet 12-LOX expressed by tumor cells in regulating ECs in cancer microvessels is emerging since 12-LOX can stimulate proliferation, migration, and tube differentiation in vitro and angiogenesis in vivo. In addition, 12-HETE upregulates expression of av b3 integrin on microvascular ECs, which is required for angio-genesis of breast cancer, whereas biosynthesis of 12-HETE by B16 melanoma cells is a determinant of their metastatic potential. Finally, 12-HETE can stimulate monocyte endothelial interactions following incubation of ECs with high glucose or minimally oxidized low-density lipoprotein, suggesting a role for LOX activation of EC in inflammatory vascular disease (Figure 4).

In summary, expression of LOX in most EC is low or absent under normal conditions. Upregulation in vivo following inflammatory challenge may result in generation of low amounts of HETEs, but it is unclear whether this is of biological significance. In contrast, generation of LOX products by adjacent cells including leukocytes and tumor cells is centrally involved in regulating microvascular EC function under pathophysiological conditions.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment