ACE phenotyping in human heart.

Leo A Bokeria,Joe G N Garcia,Sergei M Danilov,Olga V Kryukova,Olga A Kost,Aigerim Z Zholbaeva,Naida I Bulaeva,Elena Z Golukhova,Victoria E Tikhomirova

doi:10.1371/journal.pone.0181976

Abstract

AimsAngiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs.Methods and resultsWe performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10–15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. “Conformational fingerprint” of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles.ConclusionsSignificant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk.

Highlights

Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality [1]
The angiotensin II is a primary mediator of renin-angiotensin system (RAS) which is mainly produced from angiotensin I by angiotensin-converting enzyme (ACE, EC 3.4.15.1, CD143)
Angiotensin-converting enzyme (ACE) activity in the human heart homogenate was about 3-fold more than in human plasma and 8-12-fold less than in human lung (Fig 1). This estimation correlates with the density of radioligand ACE inhibitor binding sites in human heart and lung [22], as well as with high ACE RNA transcription in the lung, while negligible in the heart, as in Human Protein Atlas [23]

Summary

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality [1]. The activation of renin-angiotensin system (RAS) definitively plays an important role in the pathogenesis of atrial fibrillation [2,3,4]. Study on the transgenic mice demonstrated that the increased ACE expression in the heart might be a causative factor for AF and sudden cardiac death [5]. Both ACE inhibitors and angiotensin receptor blockers reduce AF incidence and may prevent AF-related complications in patients and in experimental models [3]

Methods

Results

Conclusion