COX-1 and Vascular Disease

Abstract

Since the discovery of the pivotal role of cyclooxygenase (COX) in the metabolism of arachidonic acid, vascular biologists have been confronted with the duality of this system. Indeed, one substrate (arachidonic acid) transformed by one enzyme (COX) yields end products (endoperoxides) that exist only very briefly before being metabolized to more stable prostanoids by a set of specific downstream synthases that were initially believed to be tissue specific. For instance, platelets contain mainly the synthase that produces thromboxane A(2) (a potent proaggregatory and vasoconstrictor substance), whereas endothelial cells contain mainly the enzyme that generates prostacyclin (an equally potent antiaggregatory and vasodilator substance). The overproduction of thromboxane A(2) by platelets leads to thrombosis; endothelial cells resist vascular occlusion by producing prostacyclin. This duality of the metabolism of arachidonic acid has dominated our thinking about atherothrombosis for decades, and rightfully still does. As scientific understanding progressed, it became evident that two isoforms of COX exist: COX-1 and COX-2. COX-1 was initially considered to be the "good," constitutive isoform, whereas COX-2 appeared to be mainly a "bad" inducible enzyme involved in inflammatory responses. However, more recently, the unexpected events resulting from the widespread use of selective COX-2 inhibitors has suggested that, from a cardiovascular point of view, the products of COX-2 exert a protective role and that this isoform cannot necessarily be regarded as "bad." Likewise, evidence has emerged that initiation of the metabolism of arachidonic acid by COX-1 is not necessarily a "good" thing in terms of vascular protection. This brief review focuses on the potential contribution of endothelial COX-1 to vascular dysfunction. It is based on a number of review articles, to which the reader will be referred in order to identify the original references to the statements made; these references are not cited here because of space limitations.

Control and Coordination of Vasomotor Tone in the Microcirculation

“…Consistent with this, in normal physiological conditions, vascular endothelial and smooth muscle cells express COX-1 (Vanhoutte, 2009). In these cells, COX-1 mainly leads to the production of PGI 2 , which www.intechopen.com induces the relaxation of smooth muscle cells by the stimulation of IP receptors (Figure 1) (Gryglewski, 2008;Vanhoutte, 2009). In contrast to COX-1, expression of COX-2 in normal blood vessels is very low (Crofford et al, 1994;Schonbeck et al, 1999).…”

“…However, COX-1 is expressed constitutively, whereas the expression of COX-2 is inducible, since the levels of this COX isoform are very low in normal conditions and its expression increases in response to pro-inflammatory stimuli (Simmons et al, 2004). Consistent with this, in normal physiological conditions, vascular endothelial and smooth muscle cells express COX-1 (Vanhoutte, 2009). In these cells, COX-1 mainly leads to the production of PGI 2 , which www.intechopen.com induces the relaxation of smooth muscle cells by the stimulation of IP receptors (Figure 1) (Gryglewski, 2008;Vanhoutte, 2009).…”

Gathering of aging and estrogen withdrawal in vascular dysfunction of senescent accelerated mice

“…Besides NO, vasoconstrictor prostaglandins have also been implicated in the phatophysiology of vascular dysfunction during aging (Briones et al, 2005;Vanhoutte, 2009) and estrogen withdrawn (Dantas et al, 1999;Dantas et al, 2004). In our studies…”

“…V asoconstrictor prostanoids, such as thromboxane A 2 (TXA2), have also been implicated in the phatophysiology of vascular dysfunction during estrogen withdrawn (Dantas et al, 1999;Dantas et al, 2004) and aging (Briones et al, 2005;Vanhoutte, 2009) and play an important role in the regulation of vascular tone in the normal systemic female vasculature (Fulton and Stallone, 2002) , which involves the TXA2 receptor (TXA2R) (Li et al, 2008) .…”

Involvement of Rac in thromboxane A2-induced human platelet activation: Regulation of sCD40 ligand release and PDGF-AB secretion

“…It has been established that human platelets mainly contain a synthase (cyclooxygenase) that generates thromboxane A 2 in the metabolism of arachidonic acid (5). Thromboxane A 2 , which is produced and released by activated human platelets, is a crucial second wave mediator that acts as a potent aggregatory agent.…”