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

Sukhbir S Dhamrait,Steve E Humphries,Hugh E Montgomery,Ulrik Pedersen-Bjergaard,Michael World,David J Brull,Cecilia Maubaret,John R Payne,Birger Thorsteinsson,Peter Gohlke

doi:10.1002/icl3.1019

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.

Highlights

Both circulating and local renin–angiotensin systems existAs a pivotal component of the endocrine renin–angiotensin systems (RAS), angiotensin-converting enzyme (ACE) plays an important role in the regulation of the human circulation
We have recently shown the combined presence of both the UCP3-55C allele and the UCP2-866A allele to be associated with gains in muscle performance following endurance training [50] in a similar pattern to that previously associated with the ACE I allele [51]
SACE activity is strongly associated with UCP2/3 genotype serum ACE (sACE) activity was normally distributed in both studies and weakly correlated with age (HMAR r = À0·19; P = 0·02, Type 1 Diabetes Mellitus Study (T1DM) r = 0·12; P = 0·04) but no other population variables

Summary

Introduction

Both circulating and local (tissue/cellular) renin–angiotensin systems existAs a pivotal component of the endocrine renin–angiotensin systems (RAS), angiotensin-converting enzyme (ACE) plays an important role in the regulation of the human circulation. Ang II provokes release of the hormone aldosterone from the adrenal glands, which leads to salt and water retention by the kidney It causes constriction of small blood vessels in the arterial tree – actions which, together, serve to elevate blood pressure. Ang II can act as an intracellular signalling molecule (so-called intracrine action): some cells internalise Ang II made elsewhere, and others synthesise it de novo (reviewed in [1]). In this way, both circulating and tissue RAS can act independently or interact in the regulation of cell function

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