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Title: Effect of streptozotocin-induced type I diabetes mellitus on the cardiac conduction system of the rat heart
Author: Zhang, Yu
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Background: Cardiovascular complications are common in type 1 diabetes mellitus and there is an increased risk of bradyarrhythmias as a result of dysfunction of the cardiac conduction system. We have shown that, in vivo, there is a decrease in the heart rate in streptozotocin-induced diabetic rats (266 ± 13 versus 316 ± 11 beats/min; P < 0.05). The aim of this study was to investigate the cellular basis of bradycardia in the rat model. Methods: Streptozotocin-induced diabetic rats were generated as described previously. Function was investigated using the Langendorff-perfused heart, isolated sinus node, and isolated sinus node cell (patch clamp). Protein expression was investigated by immunohistochemistry and Western blot. The research was conducted in accordance with legislations in the UAE and UK. Results: Compared to control rats, diabetic rats showed a 428% increase in blood glucose and 16% increase in heart-to-body-weight ratio. The heart rate measured in the Langendorff heart decreased by 17.4% in diabetic rats from 298 to 246 beats/min. The beating rate of the isolated sinus node preparation decreased by 17.3% from 305 to 252 beats/min. Application of 2 μM ryanodine to the sinus node preparation to incapacitate RyR2 caused arrhythmia in the diabetic preparations, but not in the control preparations. If was measured in the sinus node cells isolated from four control rats (n = 29 cells) and three diabetic rats (n = 33 cells). The If density and cell capacitance were significantly reduced in streptozotocin-induced type 1 diabetic rats. Immunohistochemistry and Western blot results showed that HCN4, Cav1.3, Cav3.1, Cx45, SERCA2a and NCX1 expression significantly decreased in the sinus node of streptozotocin -induced type 1 diabetic rats. RyR2, SERCA2a and NCX1 expression was significantly decreased in the atrioventricular junction. In addition, Cx40, Cx43, Cx45, RyR2, SERCA2a, Kir3.1 and a-actinin expression was significantly decreased in the Purkinje fibres. Nav1.5, RyR2, SERCA2a, NCX1 and Cx43 expression was significantly decreased in the atria and ventricle. Downregulation of NF-M and the b2-adrenergic receptor indicates reduced autonomic neuronal control. The data also showed fibrosis and apoptosis within the streptozotocin-induced type 1 diabetic rats, which could be another factor contributing to bradyarrhythmias and ventricular dysfunction. Conclusions: It is concluded that there are complex functional changes in the cardiac conduction system in diabetes. The changes in the membrane and calcium clocks in streptozotocin-induced type 1 diabetes could affect action potential generation and conduction.
Supervisor: Boyett, Mark ; Dobrzynski, Halina Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available