title: Lipoxygenase and prostaglandin G/H synthase cascades in cardiovascular disease.
abstract: The 12/15-lipoxygenase (LO) cascade governs the generation of 12-hydroperoxy-eicosatetraenoic acid (HPETE) and 15-HPETE from arachidonic acid. The 5-LO pathway plays a fundamental role in the biosynthesis of leukotrienes, essential inflammatory lipid mediators. Cyclooxygenase (COX)-1 and -2 biosynthetic pathways are responsible for prostaglandin and thromboxane formation. Experimental investigations in animal models using 12/15-LO deficient mice, 12/15-LO or 15-LO transgenic mice, or pharmacological 15-LO inhibition have all demonstrated the essential role of 12/15-LO in atherogenesis. The underlying mechanisms are linked to low-density lipoprotein oxidation, pro-inflammatory Th1 cytokine production and enhanced monocyte-endothelial cell interaction. Human genetic studies as well as disruption of the 5-LO gene in mouse models of hyperlipidemia revealed that 5-LO and 5-LO-activating protein are associated with risks of human cardiovascular disease, and that this cascade plays an important role in aortic aneurysm pathogenesis through leukotriene-mediated inflammatory chemokine production. COX-1 plays an active role in atherogenesis via thromboxane A(2), while COX-2-derived prostaglandin (PGI(2)) protects against atherosclerosis in murine models. Recent data demonstrated that selective inhibition of COX-2 augments the risk of cardiovascular events in patients. Selective inhibition or blockade of selective components in these two enzymatic pathways through systemic drug delivery or medical device approaches (e.g., drug-eluting stents) may have therapeutic benefit against certain cardiovascular diseases.
authors.affiliation: Cordis Corp., a Johnson & Johnson company, 7 Powder Horn Drive, Warren, NJ 07059, USA. lzhao5@crdus.jnj.com
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Tilo
authors.initials: T
authors.lastname: Grosser
authors.forename: Susanne
authors.initials: S
authors.lastname: Fries
authors.forename: Leena
authors.initials: L
authors.lastname: Kadakia
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zhao
authors.forename: Robert
authors.initials: R
authors.lastname: Falotico