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Inhibition of cyclooxygenase (COX)-2 increases cardiovascular deaths. Identifying a biomarker of COX-2 is desirable but difficult, since COX-1 and COX-2 ordinarily catalyze formation of an identical product, prostaglandin H2. When acetylated by aspirin, however, COX-2 (but not COX-1) can form 15(R)-HETE, which is metabolized to aspirin-triggered lipoxin (ATL), 15-epi-lipoxin A4. Here we have used COX-1- and COX-2-knockout mice to establish whether plasma ATL could be used as a biomarker of vascular COX-2 in vivo. Vascular COX-2 was low but increased by LPS (10 mg/kg; i.p). Aspirin (10 mg/kg; i.v.) inhibited COX-1, measured as blood thromboxane and COX-2, measured as lung PGE2. Aspirin also increased the levels of ATL in the lungs of LPS-treated wild-type C57Bl6 mice (vehicle: 25.5±9.3 ng/ml; 100 mg/kg: 112.0±7.4 ng/ml; P<0.05). Despite this, ATL was unchanged in plasma after LPS and aspirin. This was true in wild-type as well as COX-1-/- and COX-2-/- mice. Thus, in mice in which COX-2 has been induced by LPS treatment, aspirin triggers detectable 15-epi-lipoxin A4 in lung tissue, but not in plasma. This important study is the first to demonstrate that while ATL can be measured in tissue, plasma ATL is not a biomarker of vascular COX-2 expression. [ABSTRACT FROM AUTHOR]

In this article, the author argues that there is little difference between the cardiovascular risks associated with non-steroid anti-inflammatory drugs (NSAIDs) and COX-2 selective drugs and says the belief that there is relies on the incorrect premise that a standard dose of a NSAID inhibits COX-2 less than COX-2 drugs do. Since NSAIDs and COX-2 drugs share a similar ability, a difference in the risk of thrombotic events it must be a result of dosage and not caused by the drugs themselves.

The beneficial actions of nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to their ability to inhibit inducible COX-2 at sites of inflammation, and their side effects (e.g., gastric damage) to inhibition of constitutive COX-1. Selective inhibitors of COX-2, such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, and valdecoxib have been developed and the greatest recent growth in our knowledge in this area has been come from the clinical use of these compounds. Although clinical data indicate that COX-2 selectivity is associated with a reduction in severe gastrointestinal events, they also reveal there are roles for constitutive COX-2 within tissues such as the brain, kidney, pancreas, intestine, and blood vessels. We now better understand the roles of COX-1 and COX-2 in functions as disparate as the perception of pain and the progression of cancers. Clinical use of COX-2-selective compounds has ignited strong debates regarding potential side effects, most notably those within the cardiovascular system such as myocardial infarctions, strokes, and elevation in blood pressure. This review will discuss how the latest studies help us understand the roles of COX-1 and COX-2 and what clinically proven benefits the newer generation of COX-2-selective inhibitors offer. [ABSTRACT FROM AUTHOR]

Discusses the mechanisms by which different cyclooxygenase-2 (COX-2) products can regulate tumor cell growth. Subdivisions of prostaglandin receptors; Role of COX products in cancer; Relationship between COX-2 activity and colony stimulating factor production.

Peroxisome proliferator-activated receptor-γ (PPARγ) and inducible cyclooxygenase-2 (COX-2) are expressed in atherosclerotic lesions, particularly in the intimal monocytic and vascular smooth muscle cells. PPARγ ligands, which include endogenous COX products, induce apoptosis of vascular smooth muscle cells in culture. We therefore studied the interaction between PPARγ and inducible cyclo-oxygenase (COX-2), in rat aortic vascular smooth muscle cells (RASMCs). [ABSTRACT FROM AUTHOR]

Background: Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified.Methods and Results: Transcriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage.Conclusions: We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction. [ABSTRACT FROM AUTHOR]

Highlights: [•] We report interactions of Toll-like receptors (TLRs) with COX enzymes in vivo. [•] COX-2 was broadly induced by LPS (TLR4) but more locally by poly(I:C) (TLR3). [•] COX-1/2 deletion modified the response to TLR activation in a TLR-specific manner. [•] COX-2 deletion enhanced interferon responses to viral-type TLR3/7/9 ligands. [•] COX-2 inhibition could provide a novel anti-viral therapeutic strategy. [Copyright &y& Elsevier]

Cyclooxygenase (COX)-1 and COX-2 are centrally important enzymes within the cardiovascular system with a range of diverse, sometimes opposing, functions. Through the production of thromboxane, COX in platelets is a pro-thrombotic enzyme. By contrast, through the production of prostacyclin, COX in endothelial cells is antithrombotic and in the kidney regulates renal function and blood pressure. Drug inhibition of COX within the cardiovascular system is important for both therapeutic intervention with low dose aspirin and for the manifestation of side effects caused by nonsteroidal anti-inflammatory drugs. This review focuses on the role that COX enzymes and drugs that act on COX pathways have within the cardiovascular system and provides an in-depth resource covering COX biology and pharmacology. The review goes on to consider the role of COX in both discrete cardiovascular locations and in associated organs that contribute to cardiovascular health. We discuss the importance of, and strategies to manipulate the thromboxane: prostacyclin balance. Finally within this review the authors discuss testable COX-2-hypotheses intended to stimulate debate and facilitate future research and therapeutic opportunities within the field. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with antiinflammatory drugs," in the 2015 issue is presented.