Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs

Background —Cardiovascular side effects associated with cyclo-oxygenase-2 inhibitor drugs dominate clinical concern. Cyclo-oxygeanse-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclo-oxygeanse-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified. Methods and Results —Transcriptome analysis of wild-type and cyclo-oxygenase-2-/- mouse tissues revealed 1 gene altered in heart and aorta but >1000 genes in the renal medulla including those regulating the endogenous NO synthase inhibitors ADMA and L-NMMA; Cyclo-oxygeanse-2-/- mice had increased plasma levels of ADMA and L-NMMA and reduced endothelial NO responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors (IP-/-). Wild-type mice or human volunteers taking cyclo-oxygeanse-2 inhibitors also showed increased plasma ADMA. Endothelial NO 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 cyclo-oxygenase-2 inhibition and systemic vascular dysfunction with non-steroidal anti-inflammatory drug usage. Conclusions —We identify the endogenous eNOS inhibitor ADMA as a biomarker and mechanistic bridge between renal COX-2 inhibition and systemic vascular dysfunction.