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

Yohannes T Ghebremariam,John P Cooke,John P Higgins,Keisuke Yamada,Maike Anderssohn,Jerry C Lee,Andrew J Patterson,Rainer H Böger,Dorothee Atzler,Rani Agrawal,Christine L C Johnson,Yu Huang

doi:10.1371/journal.pone.0060653

Abstract

AimsGenetic 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 ResultsIn 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.ConclusionOur study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

Highlights

Salt-sensitivity (SS), dysregulated changes in blood pressure (BP) in response to salt-intake, is principally influenced by genetics, diet, age and socio-economic factors and is strongly associated with increased cardiovascular (CV) risk and mortality [1,2]
In this study, we evaluated the in vivo effect of INT-747 on tissue dimethylarginine dimethylaminohydrolase (DDAH) expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS)
high salt (HS) diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls

Summary

Introduction

Salt-sensitivity (SS), dysregulated changes in blood pressure (BP) in response to salt-intake, is principally influenced by genetics, diet, age and socio-economic factors and is strongly associated with increased cardiovascular (CV) risk and mortality [1,2]. High salt intake is associated with renal calculi and other kidney diseases [4,5]. In this regard, the Dietary Approaches to Stop Hypertension (DASH) study demonstrated a significant reduction in BP by reducing salt-intake and/or by consuming the ‘‘DASH diet’’ [6]; a good source of dietary nitrates which can be converted to nitric oxide (NO) in vessel walls [7].

Methods

Results

Discussion

Conclusion