title: Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.
abstract: Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to beregulated bymitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK menandScandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongstUCP3-55C(rather than T) andUCP2I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P< 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h;P< 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly,cellularUCP regulation ofsACEsuggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.
authors.affiliation: Centre for Cardiovascular Genetics, BHF Laboratories University College London London UK; Department of Cardiology Western Sussex Hospitals NHS Trust West Sussex UK.
authors.forename: Sukhbir S
authors.initials: SS
authors.lastname: Dhamrait
authors.affiliation: Centre INSERM U897-Epidemiologie-Biostatistique Bordeaux France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Maubaret
authors.affiliation: Department of Cardiology, Nephrology and Endocrinology Hillerød Hospital Hillerød Denmark; Faculty of Health Sciences University of Copenhagen Copenhagen Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Pedersen-Bjergaard
authors.affiliation: Centre for Cardiovascular Genetics, BHF Laboratories University College London London UK; Department of Cardiology The Whittington Hospital NHS Trust London UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brull
authors.affiliation: Institute of Experimental and Clinical Pharmacology University Hospital of Schleswig-Holstein Kiel Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gohlke
authors.affiliation: Centre for Cardiovascular Genetics, BHF Laboratories University College London London UK; Scottish National Advanced Heart Failure Service Golden Jubilee National Hospital Clydebank UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Payne
authors.affiliation: Royal Centre for Defence Medicine Queen Elizabeth Hospital Birmingham UK.
authors.forename: Michael
authors.initials: M
authors.lastname: World
authors.affiliation: Department of Cardiology, Nephrology and Endocrinology Hillerød Hospital Hillerød Denmark; Faculty of Health Sciences University of Copenhagen Copenhagen Denmark.
authors.forename: Birger
authors.initials: B
authors.lastname: Thorsteinsson
authors.affiliation: Centre for Cardiovascular Genetics, BHF Laboratories University College London London UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: UCL and National Centre for Sport, Exercise & Health University College London London UK; UCL Institute for Human Health and Performance University College London London UK.
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Montgomery
keywords: ACE; association studies; endothelial cell; gene expression; genetics; uncoupling protein