TY - JOUR
T1 - FXR Agonist INT-747 Upregulates DDAH Expression and Enhances Insulin Sensitivity in High-Salt Fed Dahl Rats
AU - Ghebremariam, Yohannes T.
AU - Yamada, Keisuke
AU - Lee, Jerry C.
AU - Johnson, Christine L.C.
AU - Atzler, Dorothee
AU - Anderssohn, Maike
AU - Agrawal, Rani
AU - Higgins, John P.
AU - Patterson, Andrew J.
AU - Böger, Rainer H.
AU - Cooke, John P.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/4/4
Y1 - 2013/4/4
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0060653
DO - 10.1371/journal.pone.0060653
M3 - Article
C2 - 23593273
AN - SCOPUS:84875939618
SN - 1932-6203
VL - 8
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e60653
ER -