Abstract
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. 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. 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.
Highlights
Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern
We focused on a cluster of genes (Agxt[2], Ddah[2], Prmt1) related to the turnover of methylarginines such as asymmetrical dimethylarginine (ADMA) and l-NMMA, which are inhibitors of NO synthase (NOS) enzymes
Using quantitative polymerase chain reaction, we confirmed that in COX-2–/– renal medulla expression of Prmt[1] (Figure 2C), which drives methylarginine synthesis,[29] was increased; Ddah[2], which breaks down methylarginine, was nonsignificantly increased (Figure II in the online-only Data Supplement), whereas Agxt[2], which degrades methylarginines,[29] tended to be reduced (Figure 2D)
Summary
Male or female COX-1–/– and COX-2–/– mice,[11] back-crossed for >7 generations onto a C57Bl/6J background (Harlan, UK) were used at 10 to 12 weeks of age. Littermate COX2+/+ mice from COX-2–/– colonies were used. Animals were genotyped before use.[11] Mice lacking prostacyclin receptors (IP–/–), supplied by Dr Rolf Nüsing, were on a C57BL/6 background as described.[28] Animal studies were conducted in accordance with Animals (Scientific Procedures) Act 1986, which is a UK act after local ethical review. Statistical significance (taken as P
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