Pathophysiology of Cyclooxygenases in Cardiovascular Homeostasis

Abstract

Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandin H(2) (PGH(2)), which is subsequently converted to the prostanoids PGE(2), PGI(2), PGF(2alpha), and thromboxane A(2). COX has 2 distinct membrane-anchored isoenzymes: COX-1 and COX-2. COX-1 is constitutively expressed in most normal tissues; COX-2 is highly induced by proinflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include conventional nonselective nonsteroidal anti-inflammatory drugs and selective nonsteroidal anti-inflammatory drugs, such as COX-2 inhibitors. The adverse effects of COX inhibitors on the cardiovascular system have been addressed in the last few years. In general, COX inhibitors have many effects, but those most important to the cardiovascular system can be direct (through the effects of prostanoids) and indirect (through alterations in fluid dynamics). Despite reports of detrimental human cardiovascular events associated with COX inhibitors, short, long, and lifetime preclinical toxicology studies in rodents and nonrodents have failed to identify these risks. This article focuses on the expression and function of COX enzymes in normal and pathologic conditions of the cardiovascular system and discusses the cardiovascular pathophysiologic complications associated with COX inhibition.

Cardiovascular safety of NSAIDs: Additional insights after PRECISION and point of view

“…PGH2 is metabolized by tissue‐specific isomerases such as thromboxane synthase in platelets to thromboxane (TX) A2; PGI synthase in endothelium, vascular smooth‐muscle cells, and renal cells to PGI2; and PGE synthase in gastric mucosa and renal cells to PGE2. In addition, leukocytes, vascular smooth‐muscle cells, endothelial cells, and platelets express PGE synthase and, as a result, are all capable of generating the inflammatory prostanoid PGE2 …”

“…In addition, leukocytes, vascular smooth-muscle cells, endothelial cells, and platelets express PGE synthase and, as a result, are all capable of generating the inflammatory prostanoid PGE2. [3][4][5][6] TXA2 induces platelet aggregation and vasoconstriction (prothrombotic effects), and PGI2 induces vasodilation and nitric oxide generation and inhibits platelet aggregation (antithrombotic effects).…”

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

“…Transgenic expression of 12/15LOX specifically in cardiomyocytes versus macrophage results in divergent effects on atheroprogressive inflammation and atherogenic cardiac pathology [11]. Disruption of LOXs, COX, and CYPs alters the metabolic transformation of arachidonic acid or other essential fatty acids to lipid mediators that have differential effects on resolving and non-resolving inflammatory responses [12-14]. …”

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors

“…1, 2 Each of these products contributes to important cellular activities for homeostasis and cell signaling. 3,4 Specifically, the role of PGE 2 in nociception has drawn significant attention, and PGE 2 signaling has been hypothesized as the mechanism by which COX inhibitors exert analgesic activity. 5 In fact, recent analysis of COX inhibitors has revealed a correlation between the reduction of PGE 2 production in bacterial lipopolysaccharide (LPS) stimulated human whole blood and the corresponding drug plasma concentrations need for analgesic efficacy in humans.…”