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Author Notes:

E-mail: john.cooke@stanford.edu

Author Contributions: Conceived the idea, designed experiments, involved in data collection, data analysis and interpretation: YTG KY JPC.

Involved in data collection: JCL CLCJ RA. Involved in data collection and critical revision of manuscript: DA MA RHB.

Involved in data collection and data analysis: JPH. Provided financial support and final approval of manuscript: AJP JPC..

Conceived and designed the experiments: YTG KY JPC. Performed the experiments: YTG KY RA CLCJ JCL RA DA MA JPH.

Analyzed the data: YTG KY DA MA RA JPH JPC. Contributed reagents/materials/analysis tools: YTG KY DA MA RHB JPH AJP JPC.

Wrote the paper: YTG JPC.

Acknowledgments: The authors are grateful to Intercept Pharmaceuticals for kindly providing INT-747 for the study.

We are also grateful to the laboratory of Dr Philip Tsao (Stanford) for providing us access to their glucometer and tissue homogenizer equipments.

We thank Stanford University Cardiovascular Institute for overall support and the Department of Comparative Medicine for immunohistochemical stainings.

Competing Interests: The INT-747 used in this study was provided by Intercept Pharmaceuticals. JPC and YTG are inventors on patents, owned by Stanford University, that protect the use of agents that therapeutically modulate the DDAH/NOS pathway.

This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Other than the listed authors, no individual employed or contracted by the sponsors played any role in: study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects:

Research Funding:

This work was supported in part by grants to JPC from the National Institutes of Health (NIH) (grant numbers RC2HL103400, 1U01HL100397, K12HL087746 and 1R01EY02060901A1); the American Heart Association (AHA) (grant number 11IRG5180026); Stanford SPARK Translational Research Program; and by the Tobacco-Related Disease Research Program of the University of California (grant number 18XT-0098). YTG was a recipient of the Stanford School of Medicine Dean’s fellowship (grant number 1049528-149- KAVFB); and is currently supported by Tobacco-Related Disease Research Program of the University of California (grant number 20FT-0090).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • NITRIC-OXIDE SYNTHASE
  • FARNESOID-X-RECEPTOR
  • DIMETHYLARGININE DIMETHYLAMINOHYDROLASE DDAH
  • TYPE-2 DIABETES-MELLITUS
  • ASYMMETRIC DIMETHYLARGININE
  • BLOOD-PRESSURE
  • DIETARY-SODIUM
  • EXPERIMENTAL-HYPERTENSION
  • SYNTHESIS INHIBITION
  • RESISTANCE

FXR Agonist INT-747 Upregulates DDAH Expression and Enhances Insulin Sensitivity in High-Salt Fed Dahl Rats

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Journal Title:

PLoS ONE

Volume:

Volume 8, Number 4

Publisher:

, Pages e60653-e60653

Type of Work:

Article | Final Publisher PDF

Abstract:

Aims:Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity.Methods and Results:In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls.Conclusion:Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

Copyright information:

© 2013 Ghebremariam et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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