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Altered Asymmetric Dimethyl Arginine Metabolism in Allergically Inflamed Mouse Lungs

¹ Centre for Translational Research in Asthma and Lung Disease, Institute of Genomics and Integrative Biology, Delhi, India

Correspondence and requests for reprints should be addressed to Anurag Agrawal, M.D., Ph.D., Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India. E-mail: a.agrawal{at}igib.res.in

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), causes uncoupling of NOS leading to generation of reactive nitrogen species, such as peroxynitrite. The lung generates a significant amount of ADMA, potentially contributing to plasma ADMA levels that have been related to endothelial dysfunction. ADMA infusion causes increased collagen deposition in lungs, suggesting that it could influence the development of chronic lung diseases such as fibrosis, chronic obstructive pulmonary disease, and asthma. To explore the link between endogenous ADMA and asthma, we determined the levels of ADMA, enzymes implicated in its metabolism, and peroxynitrite in murine models of allergic airway inflammation (AAI) resembling asthma. ADMA levels and nitrosative stress were found to be positively correlated in cytosol and mitochondria during AAI. This was associated with increased expression of protein–arginine methyltransferase-2, an ADMA-synthesizing enzyme, and reduced expression of dimethylarginine dimethylaminohydrolase-2, an ADMA-degrading enzyme, in bronchial epithelia. Increased nitrotyrosine similarly localized to the bronchial epithelium, as well as in infiltrated inflammatory cells. Administration of L-arginine, which was expected to compete with ADMA and reverse the uncoupling/inhibition of NOS, restored normal ADMA metabolism, along with the expected reduction of nitrosative stress in lung. Because dimethylarginine dimethylaminohydrolase-2 function is known to be negatively related to oxidative stress, this may represent a feed-forward loop effect. We conclude that a delicate balance between ADMA-metabolizing enzymes is disturbed in bronchial epithelium during AAI, potentially causing increased nitrosative stress in a self-propagating cycle. This represents a potential therapeutic target in asthma.

Key Words: assymetric dimethylarginine • protein arginine methyl transferase • dimethylarginine dimethyl aminotransferase • peroxynitrite • asthma

CLINICAL RELEVANCE Altered regulation of asymmetric dimethylarginine (ADMA) metabolizing enzymes in bronchial epithelia leads to increased production of ADMA, and this may perpetuate the nitrosative stress by nitric oxide (NO) synthase uncoupling in allergic airway inflammation. These may underlie many of the pathophysiological associations of NO in a mouse model of asthma, and represent therapeutic targets.