The Role Of Adma Metabolism In The Regulation Of Human Pulmonary Endothelial Cell Function

Objective: Asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication required for the coordinated regulation of pulmonary endothelial permeability and angiogenesis, contributing to the disease. Methods and Results. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells (HPAECs). ADMA inhibited protein expression and cell surface localization of connexin 43 (Cx43) in HPAECs (2-fold decrease, P In vivo lung permeability was increased in DDAHI homozygous knockout mice (1.2-fold increase, P Conclusions. ADMA is critical in the regulation of gap junctional communication in pulmonary endothelium. Endothelial cells from IPAH patients show reduced ADMA metabolism resulting in defective gap junctional communication and abnormal angiogenic responses. Enhancing Cx43 function may have endothelium-protective effects in conditions associated with reduced nitric oxide signalling, such as pulmonary hypertension.