Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA

Bulau, P., Zakrzewicz, D., Kitowska, K., Leiper, J. , Gunther, A., Grimminger, F. and Eickelberg, O. (2007) Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. American Journal of Physiology: Lung Cellular and Molecular Physiology, 292(1), L18-L24. (doi:10.1152/ajplung.00076.2006) (PMID:16891395)

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Abstract

Protein arginine methylation is catalyzed by a family of enzymes called protein arginine methyltransferases (PRMTs). Three forms of methylarginine have been identified in eukaryotes: monomethylarginine (l-NMMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), all characterized by methylation of one or both guanidine nitrogen atoms of arginine. l-NMMA and ADMA, but not SDMA, are competitive inhibitors of all nitric oxide synthase isoforms. SDMA is eliminated almost entirely by renal excretion, whereas l-NMMA and ADMA are further metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To explore the interplay between methylarginine synthesis and degradation in vivo, we determined PRMT expression and DDAH activity in mouse lung, heart, liver, and kidney homogenates. In addition, we employed HPLC-based quantification of protein-incorporated and free methylarginine, combined with immunoblotting for the assessment of tissue-specific patterns of arginine methylation. The salient findings of the present investigation can be summarized as follows: 1) pulmonary expression of type I PRMTs was correlated with enhanced protein arginine methylation; 2) pulmonary ADMA degradation was undertaken by DDAH1; 3) bronchoalveolar lavage fluid and serum exhibited almost identical ADMA/SDMA ratios, and 4) kidney and liver provide complementary routes for clearance and metabolic conversion of circulating ADMA. Together, these observations suggest that methylarginine metabolism by the pulmonary system significantly contributes to circulating ADMA and SDMA levels.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Bulau, P., Zakrzewicz, D., Kitowska, K., Leiper, J., Gunther, A., Grimminger, F., and Eickelberg, O.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Physiology: Lung Cellular and Molecular Physiology
Publisher:American Physiological Society
ISSN:1040-0605
ISSN (Online):1522-1504
Published Online:10 January 2007

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