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Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease

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Abstract

It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from l-arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH2) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

AGAT:

Arginineglycine amidinotransferase

CAD:

Coronary artery disease

CVD:

Cardiovascular disease

DDAH:

Dimethylarginine dimethylaminohydrolase

FMD:

Flow-mediated dilatation

GAMT:

Guanidinoacetate methyltransferase

hArg:

Homoarginine

IMT:

Intima-media thickness

MMA:

Monomethylarginine

NO:

Nitric oxide

NOS:

NO synthase

eNOS:

Endothelial nitric oxide synthase

nNOS:

Neuronal nitric oxide synthase

PCI:

Percutaneous coronary intervention

PRMTs:

Protein arginine N-methyltransferases

ROS:

Reactive oxygen species

SDMA:

Symmetric dimethylarginine

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  1. 1st Cardiology Department, Athens University Medical School, Vasilisis Sofias 114, Athens, Greece

    Nikolaos Papageorgiou, Emmanuel Androulakis, Spyridon Papaioannou, Charalambos Antoniades & Dimitris Tousoulis

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  1. Nikolaos Papageorgiou
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  2. Emmanuel Androulakis
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  3. Spyridon Papaioannou
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  4. Charalambos Antoniades
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  5. Dimitris Tousoulis
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Correspondence to Dimitris Tousoulis.

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Papageorgiou, N., Androulakis, E., Papaioannou, S. et al. Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease. Amino Acids 47, 1741–1750 (2015). https://doi.org/10.1007/s00726-015-2017-y

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