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 be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (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, cellular UCP regulation of sACE suggests 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
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071245:Mitochondrial Uncoupling Proteins / Q000235:genetics*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000071245:Mitochondrial Uncoupling Proteins; D007703:Peptidyl-Dipeptidase A
keywords: ACE; association studies; endothelial cell; gene expression; genetics; uncoupling protein