Effect of Lowering Asymmetric Dimethylarginine (ADMA) on Vascular Pathology in Atherosclerotic ApoE-Deficient Mice with Reduced Renal Mass

Johannes Jacobi,Karl Hilgers,Renke Maas,Nada Cordasic,Michaela Arend

doi:10.3390/ijms15045522

Effect of Lowering Asymmetric Dimethylarginine (ADMA) on Vascular Pathology in Atherosclerotic ApoE-Deficient Mice with Reduced Renal Mass

Johannes Jacobi, Karl Hilgers + Show 3 more

Open Access

https://doi.org/10.3390/ijms15045522

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Abstract

The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n = 39) and C57Bl/6J wild-type littermates (WT, n = 27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n = 11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model.

Highlights

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a novel biomarker in cardiovascular disease [1]
ADMA does not derive from direct methylation of free L-arginine, but is rather generated from the posttranslational methylation of L-arginine residues within proteins catalyzed by a family of enzymes, called protein arginine methyltransferases (PRMT) [7]
ADMA is in part cleared from the circulation via renal excretion and hepatic metabolism; the vast majority is metabolized via enzymatic degradation through an enzyme called dimethylarginine dimethylaminohydrolase (DDAH)

Summary

Introduction

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a novel biomarker in cardiovascular disease [1]. Based on substrate and product specificity, PRMTs are divided into enzymes with Type I or Type II activity Both types form monomethyl L-arginine (L-NMMA), but differ in that Type I enzymes produce ADMA, whereas Type II enzymes generate symmetrical dimethylarginine (SDMA) [7]. ADMA is in part cleared from the circulation via renal excretion and hepatic metabolism; the vast majority is metabolized via enzymatic degradation through an enzyme called dimethylarginine dimethylaminohydrolase (DDAH). This enzyme, of which two isoforms with distinct tissue distribution have been identified, catalyzes the hydrolysis of L-NMMA and ADMA into L-citrulline and mono- or di-methylamine [8]

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