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The role of l-arginine/l-homoarginine/nitric oxide pathway for aortic distensibility and intima-media thickness in stroke patients

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Abstract

Asymmetric dimethylarginine (ADMA) and l-homoarginine (hArg) are l-arginine (Arg) metabolites derived from different pathways. Protein arginine N-methyltransferase (PRMT) and subsequent proteolysis of proteins containing methylarginine residues release ADMA. Arginine:glycine amidinotransferase (AGAT) converts Arg to hArg and guanidinoacetate (GAA). While high concentrations of ADMA and low concentrations of hArg in the blood have been established as cardiovascular risk markers, the cardiovascular relevance of GAA is still unexplored. Arg and hArg are substrates and ADMA is an inhibitor of nitric oxide (NO) synthase (NOS). The cardiovascular effects of ADMA and hArg have been related to NO, a potent endogenous vasodilator. ADMA and hArg are considered to exert additional, not yet explored, presumably NO-unrelated effects and to act antagonistically in the renal and cardiovascular systems. Although the physiological role of Arg, ADMA, hArg and NO for endothelial function in small- and medium-sized arteries has been intensively studied in the past, the clinical relevance of aortic wall remodeling still remains unclear. Here, we evaluated potential relation between aortic distensibility (AD) or aortic intima-media thickness (aIMT) and circulating ADMA, hArg, GAA, and the NO metabolites nitrite and nitrate in the plasma of 78 patients (24 females, 54 males; aged 59 ± 14 years) with recent ischemic stroke or transient ischemic attack (TIA). All biochemical parameters were determined by stable-isotope dilution gas chromatography–mass spectrometry. AD and aIMT were measured by transesophageal echocardiography. Arg, hArg, ADMA and GAA median plasma concentrations (µM) were determined to be 61, 1.43, 0.50 and 2.16, respectively. hArg, ADMA and GAA correlated closely with Arg. Nitrite, nitrate and creatinine median plasma concentrations (µM) were 2.49, 48.7, and 84.1, respectively. Neither AD (2.61 vs. 1.85 10−6 × cm2 × dyn−1, P = 0.064) nor aIMT (1.25 vs. 1.13 mm, P = 0.596) differed between females and males. The hArg/ADMA molar ratio (r = −0.351, P = 0.009), nitrate (r = 0.364, P = 0.007) and nitrite (r = 0.329, P = 0.015) correlated with aIMT but not with AD. Arg, hArg, ADMA and GAA correlated with aIMT but not with AD. The results demonstrate a strong relation between the Arg/NO pathway and aortic atherosclerosis but not with AD suggesting different mechanisms underlying the two aspects of aortic wall remodeling.

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Abbreviations

AD:

Aortic distensibility

ADMA:

Asymmetric dimethylarginine

AGAT:

Arginine:glycine amidinotransferase

CVD:

Cerebrovascular disease

GAA:

Guanidinoacetate

GAMT:

Guanidinoacetate N-methyltransferase

GC–MS:

Gas chromatography–mass spectrometry

hArg:

Homoarginine

IGF-1:

Insulin-like growth factor 1

IMT:

Intima-media thickness

aIMT:

Aortic intima-media thickness

INR:

International normalized ratio

NO:

Nitric oxide

NOS:

Nitric oxide synthase

QC:

Quality control

TIA:

Transient ischemic attack

TOE:

Transesophageal echocardiography

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Acknowledgements

This work is part of the medical doctoral thesis of Georgi Radoslavov Yanchev, which was performed at the Centre of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany, under the supervision of Dimitrios Tsikas and Arash Haghikia. Arash Haghikia is supported by the “Junge Akademie” Program of the Hannover Medical School.

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    Authors and Affiliations

    1. Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

      Arash Haghikia, Nils Bledau, Christian Widera, Kristina Sonnenschein, Johann Bauersachs & Udo Bavendiek

    2. Department of Cardiology, Charité Universitätsmedizin Berlin (Campus Benjamin Franklin), Berlin, Germany

      Arash Haghikia

    3. Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

      Georgi Radoslavov Yanchev, Arslan Arinc Kayacelebi, Erik Hanff & Dimitrios Tsikas

    4. Department of Cardiology, Heart Center Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany

      Christian Widera

    5. Department of Neurology, Ruhr-University Bochum, Bochum, Germany

      Aiden Haghikia

    6. Department of Neurology, Hannover Medical School, Hannover, Germany

      Karin Weissenborn

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    1. Arash Haghikia
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    Correspondence to Dimitrios Tsikas.

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    The study reported here was approved by the Ethics Committee of the Hannover Medical School. All participants gave their written informed consent.

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    A. Haghikia and G. R. Yanchev contributed equally to this work and are both first authors.

    D. Tsikas and U. Bavendiek are both senior authors.

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    Haghikia, A., Yanchev, G.R., Kayacelebi, A.A. et al. The role of l-arginine/l-homoarginine/nitric oxide pathway for aortic distensibility and intima-media thickness in stroke patients. Amino Acids 49, 1111–1121 (2017). https://doi.org/10.1007/s00726-017-2409-2

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