ACE gene dosage determines additional autonomic dysfunction and increases renal angiotensin II levels in diabetic mice

Oscar Albuquerque De Moraes,Karin Flues,Kátia Bilhar Scapini,Cristiano Mostarda,Fabiana De Sant'Anna Evangelista,Bruno Rodrigues,Daniela Ravizzoni Dartora,Patricia Fiorino,Kátia De Angelis,Maria Cláudia Irigoyen

doi:10.6061/clinics/2018/e246

Abstract

OBJECTIVES:The present study aimed to investigate cardiovascular autonomic modulation and angiotensin II (Ang II) activity in diabetic mice that were genetically engineered to harbor two or three copies of the angiotensin-converting enzyme gene.METHODS:Diabetic and non-diabetic mice harboring 2 or 3 copies of the angiotensin-converting enzyme gene were used in the present study. Animals were divided into 4 groups: diabetic groups with two and three copies of the angiotensin-converting enzyme gene (2CD and 3CD) and the respective age-matched non-diabetic groups (2C and 3C). Hemodynamic, cardiovascular, and autonomic parameters as well as renal Ang II expression were evaluated.RESULTS:Heart rate was lower in diabetic animals than in non-diabetic animals. Autonomic modulation analysis indicated that the 3CD group showed increased sympathetic modulation and decreased vagal modulation of heart rate variability, eliciting increased cardiac sympathovagal balance, compared with all the other groups. Concurrent diabetes and either angiotensin-converting enzyme polymorphism resulted in a significant increase in Ang II expression in the renal cortex.CONCLUSION:Data indicates that a small increase in angiotensin-converting enzyme activity in diabetic animals leads to greater impairment of autonomic function, as demonstrated by increased sympathetic modulation and reduced cardiac vagal modulation along with increased renal expression of Ang II.

Highlights

IntroductionThe clinical relevance of the angiotensin converting enzyme (ACE) polymorphism was first described in 1990, when Rigat et al [1] found a 2-fold increase in serum ACE levels in patients with the ACE DD genotype compared with ACE II patients
There were no differences in blood pressure values between the groups; a lower heart rate (HR) was detected in diabetic animals than in control animals (Table 1)
The present study was the first to demonstrate that STZinduced diabetic mice with 3 copies of the angiotensin converting enzyme (ACE) gene presented increased sympathetic modulation and reduced vagal modulation of the heart

Summary

Introduction

The clinical relevance of the angiotensin converting enzyme (ACE) polymorphism was first described in 1990, when Rigat et al [1] found a 2-fold increase in serum ACE levels in patients with the ACE DD genotype compared with ACE II patients. In concordance with Rigat et al, in recent years, several studies have demonstrated an association of the DD genotype. Received for publication on June 28, 2017. Accepted for publication on February 5, 2018. Observational data demonstrated an elevated frequency of the ACE DD genotype in type 2 diabetes patients [5]

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