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Inside Cell. 2016 Jan;1(1):70-81. Epub 2015 Aug 2.

Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

Author information

1
Centre for Cardiovascular Genetics, BHF LaboratoriesUniversity College LondonLondonUK; Department of CardiologyWestern Sussex Hospitals NHS TrustWest SussexUK.
2
Centre INSERM U897-Epidemiologie-Biostatistique Bordeaux France.
3
Department of Cardiology, Nephrology and EndocrinologyHillerød HospitalHillerødDenmark; Faculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark.
4
Centre for Cardiovascular Genetics, BHF LaboratoriesUniversity College LondonLondonUK; Department of CardiologyThe Whittington Hospital NHS TrustLondonUK.
5
Institute of Experimental and Clinical Pharmacology University Hospital of Schleswig-Holstein Kiel Germany.
6
Centre for Cardiovascular Genetics, BHF LaboratoriesUniversity College LondonLondonUK; Scottish National Advanced Heart Failure ServiceGolden Jubilee National HospitalClydebankUK.
7
Royal Centre for Defence Medicine Queen Elizabeth Hospital Birmingham UK.
8
Centre for Cardiovascular Genetics, BHF Laboratories University College London London UK.
9
UCL and National Centre for Sport, Exercise & HealthUniversity College LondonLondonUK; UCL Institute for Human Health and PerformanceUniversity College LondonLondonUK.

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.

KEYWORDS:

ACE; association studies; endothelial cell; gene expression; genetics; uncoupling protein

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