Key result
Carriage of UCP3-55C and UCP2 I alleles was associated with higher serum ACE activity, and RNA interference against UCP2 in endothelial cells increased ACE expression (<1.8-fold; P<0.01).
Mitochondrial uncoupling proteins appear to regulate ACE expression, suggesting a novel cellular feedback mechanism and crosstalk between cellular and endocrine metabolism.
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Hypothesis-generating for UCP-ACE crosstalk in endothelial cells; leaves open relevance to human cardiovascular outcomes or therapy.
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.
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Dhamrait et al. (2016) studied Healthy and diabetic. UCP3-55C and UCP2 I alleles / UCP2 RNA interference vs. UCP3-55T and UCP2 D alleles / control was evaluated on Serum ACE activity and ACE expression (<1.8-fold increase, p=<0.01). Carriage of UCP3-55C and UCP2 I alleles was associated with higher serum ACE activity, and RNA interference against UCP2 in endothelial cells increased ACE expression (<1.8-fold; P<0.01).
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