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Plasma asymmetric and symmetric dimethylarginine in a rat model of endothelial dysfunction induced by acute hyperhomocysteinemia

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Abstract

Hyperhomocysteinemia induces vascular endothelial dysfunction, an early hallmark of atherogenesis. While higher levels of circulating asymmetric dimethylarginine (ADMA) and symmetric dimethyl arginine (SDMA), endogenous inhibitors of nitric oxide synthesis, have been associated with increased cardiovascular risk, the role that ADMA and SDMA play in the initiation of hyperhomocysteinemia-induced endothelial dysfunction remains still controversial. In the present study, we studied the changes of circulating ADMA and SDMA in a rat model of acutely hyperhomocysteinemia-induced endothelial dysfunction. In healthy rats, endothelium-related vascular reactivity (measured as acetylcholine-induced transient decrease in mean arterial blood pressure), plasma ADMA and SDMA, total plasma homocysteine (tHcy), cysteine and glutathione were measured before and 2, 4 and 6 h after methionine loading or vehicle. mRNA expression of hepatic dimethylarginine dimethylaminohydrolase-1 (DDAH1), a key protein responsible for ADMA metabolism, was measured 6 h after the methionine loading or the vehicle. Expectedly, methionine load induced a sustained increase in tHcy (up to 54.9 ± 1.9 µM) and a 30 % decrease in vascular reactivity compared to the baseline values. Plasma ADMA and SDMA decreased transiently after the methionine load. Hepatic mRNA expression of DDAH1, cathepsin D, and ubiquitin were significantly lower 6 h after the methionine load than after the vehicle. The absence of an elevation of circulating ADMA and SDMA in this model suggests that endothelial dysfunction induced by acute hyperhomocysteinemia cannot be explained by an up-regulation of protein arginine methyltransferases or a down-regulation of DDAH1. In experimental endothelial dysfunction induced by acute hyperhomocysteinemia, down-regulation of the proteasome is likely to dampen the release of ADMA and SDMA in the circulation.

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Abbreviations

Ach:

Acetylcholine

ADMA:

Asymmetric dimethylarginine

DDAH:

Dimethylarginine dimethylaminohydrolase

DMA:

Dimethylarginine

MAP:

Mean arterial pressure

NO:

Nitric oxide

PRMT:

Protein arginine methyltransferase

ROS:

Reactive oxygen species

SAM:

S-adenosylmethionine

SDMA:

Symmetric dimethylarginine

tHCy:

Total plasma homocysteine

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Acknowledgments

We thank Maëlle Robert for her contribution to the experimentation and Dominique Hermier for the help with the collection of the tissue samples. This work was supported by the French Ministry of Research. J. Magné is supported by the Swedish Heart–Lung Foundation, the Fredrik and Ingrid Thuring Foundation, and the Lars Hiertas Minne Foundation.

Conflict of interest

None of the authors had a conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the guidelines issued by the French National Animal Care Committee at which the studies were conducted.

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Authors and Affiliations

  1. Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, 171 76, Stockholm, Sweden

    Joëlle Magné

  2. AgroParisTech, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, 16 rue Claude Bernard, 75005, Paris, France

    Jean-François Huneau, Véronique Mathé, Cécile Bos & François Mariotti

  3. INRA, CRNH-IdF, UMR914 Nutrition Physiology and Ingestive Behavior, 16 rue Claude Bernard, 75005, Paris, France

    Jean-François Huneau, Véronique Mathé, Cécile Bos & François Mariotti

  4. Laboratoire de Biochimie, Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Assistance Publique-Hôpitaux de Paris (AP-HP), 75679, Paris Cedex 14, France

    Didier Borderie

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  1. Joëlle Magné
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  2. Jean-François Huneau
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  3. Didier Borderie
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Correspondence to François Mariotti.

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Magné, J., Huneau, JF., Borderie, D. et al. Plasma asymmetric and symmetric dimethylarginine in a rat model of endothelial dysfunction induced by acute hyperhomocysteinemia. Amino Acids 47, 1975–1982 (2015). https://doi.org/10.1007/s00726-015-1959-4

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  • DOI: https://doi.org/10.1007/s00726-015-1959-4

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