Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart.

Yu Zhang,Hong Sun,Joseph Yanni,Mohammed Anwar Qureshi,Yanwen Wang,Sarah Kassab,Mark R Boyett,Halina Dobrzynski,Sunil Jit R J Logantha,Frank Christopher Howarth,Natalie J Gardiner

doi:10.3389/fphys.2019.00826

Abstract

Cardiovascular complications are common in type 1 diabetes mellitus (TIDM) and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS). We have previously shown that, in vivo, there is a decrease in the heart rate and prolongation of the QRS complex in streptozotocin-induced type 1 diabetic rats indicating dysfunction of the CCS. The aim of this study was to investigate the function of the ex vivo CCS and key proteins that are involved in pacemaker mechanisms in TIDM. RR interval, PR interval and QRS complex duration were significantly increased in diabetic rats. The beating rate of the isolated sinoatrial node (SAN) preparation was significantly decreased in diabetic rats. The funny current density and cell capacitance were significantly decreased in diabetic nodal cells. Western blot showed that proteins involved in the function of the CCS were significantly decreased in diabetic rats, namely: HCN4, Cav1.3, Cav3.1, Cx45, and NCX1 in the SAN; RyR2 and NCX1 in the atrioventricular junction and Cx40, Cx43, Cx45, and RyR2 in the Purkinje network. We conclude that there are complex functional and cellular changes in the CCS in TIDM. The changes in the proteins involved in the function of this electrical system are expected to adversely affect action potential generation and propagation, and these changes are likely to be arrhythmogenic.

Highlights

The cardiac conduction system (CCS) is a network of specialized myocytes with unique molecular, anatomical, and functional properties that enable them to function as the electrical system of the heart
There seem to be two separate but closely communicating mechanisms: a “membrane clock” which consists of Streptozotocin-Induced Diabetes and Cardiac Conduction System ion channels
We have previously shown that Type I diabetes mellitus (TIDM) affects a range of mRNA expression in the diabetic sinoatrial node (SAN) (NCX1, Cx45, Cav3.1, and HCN4) (Ferdous et al, 2016; Huang et al, 2017)

Summary

Introduction

The cardiac conduction system (CCS) is a network of specialized myocytes with unique molecular, anatomical, and functional properties that enable them to function as the electrical system of the heart. The CCS includes the sinoatrial node (SAN), atrioventricular junction (AVJ), bundle branches (BB), and Purkinje fibers (PF) (Stephenson et al, 2017). There seem to be two separate but closely communicating mechanisms ( termed as “clocks”): a “membrane clock” which consists of Streptozotocin-Induced Diabetes and Cardiac Conduction System ion channels (hyperpolarization-activated cyclic nucleotidegated channels, mainly HCN4, L-type Ca2+ channels, mainly Cav1.3, and T-type Ca2+ channels, mainly Cav3.1 and a “calcium clock” which consists of Ca2+ – handling proteins (ryanodine receptor, RyR2, sarcoplasmic reticulum-ATPase, SERCA2a, and Na+/Ca2+ exchanger, and NCX1). The cells of the CCS communicate via gap junctional channels made of connexins (Cx40, Cx43, and Cx45) (Monfredi et al, 2013). Type I diabetes mellitus (TIDM) is associated with cardiovascular complications, including cardiac arrhythmias, QT interval prolongation and sudden cardiac death (Nobe et al, 1990). Research has demonstrated that AV node block (Rubler et al, 1975) and bradyarrhythmias (Grimm et al, 1990) are significantly high in the diabetes mellitus (DM) population

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