Genetic and molecular determinants of atherosclerotic plaque instability.
Arachidonic acid metabolism plays a key role in atherothrombotic events affecting the coronary or cerebrovascular territory, as reflected by experimental studies based on biochemical measurements of eicosanoid biosynthesis and the results of inhibitor trials in these settings. Two cyclooxygenase (COX)-isozymes exist, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, and susceptibility to inhibition by drugs. Whereas the role of COX-1 expressed in platelets in acute coronary syndromes and ischemic stroke is definitely established through several large clinical studies with aspirin, the role of COX-2 activity in these settings is still unclear, because this enzyme was characterized only recently (1991) and its inhibitors (coxibs) only became available in 1998. In this review, we discuss the different expression profile of COX-2-related enzymes in the cells actively involved in atherothrombosis, the role of these enzymes as cause of plaque "instability", and the clinical consequences of their inhibition. Recent studies suggest that variable expression of transmembrane and downstream receptors, as well as genetic mutations represent important determinants of the functional consequences of COX-2 expression and inhibition in different clinical settings.
Cipollone
Francesco
F
Center of Excellence on Atherosclerosis, Hypertension and Dyslipidemia, University of Chieti G. d'Annunzio, Chieti, Italy. fcipollone@unich.it
Toniato
Elena
E
Martinotti
Stefano
S
Mezzetti
Andrea
A
D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D012422:Rupture, Spontaneous / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013927:Thrombosis / Q000235:genetics / Q000503:physiopathology
D001095:Arachidonic Acids; D052246:Cyclooxygenase 2 Inhibitors; D000067759:Receptor for Advanced Glycation End Products; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D011971:Receptors, Immunologic; D051546:Cyclooxygenase 2