Endothelial Cell

Miqration

Tube differentiation Angiogenic

Miqration

Tube differentiation Angiogenic

Figure 4 Signaling properties of 12-HETE in endothelial cells. The LOX product 12-HETE induces multiple biological effects in endothelium. (see color insert)

Figure 5 Localization of CYP isoforms in vascular tissue. Endothelium contains a number of CYP enzymes that generate bioactive lipid products. An additional important isoform is CYP4A, in smooth muscle that generates 20-HETE. TXS, thromboxane synthase; EET, epoxyeicosatetraenoic acid; DHET, dihydroxyeicosate-traenoic acid. (see color insert)

Figure 5 Localization of CYP isoforms in vascular tissue. Endothelium contains a number of CYP enzymes that generate bioactive lipid products. An additional important isoform is CYP4A, in smooth muscle that generates 20-HETE. TXS, thromboxane synthase; EET, epoxyeicosatetraenoic acid; DHET, dihydroxyeicosate-traenoic acid. (see color insert)

(LOO^) radicals that are ultimately converted into hydroperoxides (LOOH) before release from the active site. At low O2 tension, a small proportion of lipid radicals (up to 10%) escape the active site. These react with O2 at diffusion-controlled rates to form free LOO\ which can then propagate secondary nonenzymatic lipid peroxidation. During this, a proportion of racemic products is formed. This reaction may be a significant source of LOOH in late atherosclerosis where lipid peroxidation product specificity is lost.

Although they do not directly bind or activate O2, PGHS and LOX can generate O/" through secondary side reactions involving oxidation of certain peroxidase substrates. In these reactions, substrates including NAD(P)H and GSH are oxidized to radicals [i.e., NAD(Py and GS\ respectively] that can ultimately react with O2 either directly, or indirectly forming O/". To date, these reactions have only been observed using purified enzyme and it is unknown whether they contribute to free radical levels in intact cells or tissue. Finally, it has been suggested that CYP2C9 is a significant source of reactive oxygen species in porcine coronary arteries that may play a role in regulating vascular tone.

in multiple ways including scavenging of the catalytic tyro-syl radical and acting as a reducing peroxidase substrate. In contrast to its lack of effect on purified PGHS, NO has multiple and often contradictory effects on PGHS expression and activity in intact cells. In several systems (including purified recombinant COX-2, intact platelets, endothelial cells, RAW-264.7 cells, an ex vivo model of renal inflammation, and following in vivo administration of •NO donors to rats), •NO highly stimulates PG production. However, other investigators have found •NO either to be inhibitory towards PGHS, or to have no effect on either PGHS activity (platelets) or LPS-induced expression in RAW-264.7 cells. In some cell types however (rat microglial cells and peritoneal macrophages), •NO suppresses LPS-induced COX-2 expression, resulting in apparent enzyme inhibition. Finally, •NO inhibits CYP through formation of an iron-nitrosyl complex, and perhaps additional uncharacterized mechanisms. In rat renal microvessels, this attenuates EET-depend-ent dilation, but conversely inhibits 20-HETE-dependent vasoconstriction through inhibition of CYP4A.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

Get My Free Ebook


Post a comment