Graduation Date

Fall 12-15-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Yu-Long Li

Second Advisor

Aaron N. Barksdale

Third Advisor

Lie Gao

Fourth Advisor

Guoku Hu

Abstract

Diabetes is the eighth leading cause of death in the United States. Every eight seconds a person dies from diabetes around the world. Among various types of diabetes, type 2 diabetes mellitus (T2DM) is the most common form, representing 90% to 95% of all diabetes populations. The leading cause of mortality and morbidity in T2DM patients is cardiovascular disease, among which acute myocardial infarction (MI)-induced ventricular arrhythmia is the major cause of death in T2DM. Patients with T2DM are two to four times more likely to die from MI than non-diabetic patients. Although well-known therapies including better glycemic control have been noted in patients with T2DM, clinical studies showed that intensive glucose control failed to reduce MI-related mortality in patients with T2DM. Withdrawal of cardiac vagal (parasympathetic) activity is a common complication in T2DM patients and is associated with arrhythmia-related sudden cardiac death (SCD) in T2DM patients. Cell excitability of cardiac vagal postganglionic (CVP) neurons located in intracardiac ganglia (ICG) is a pivotal factor for acetylcholine (ACh) release from cardiac vagal nerve terminals and the resultant regulation of cardiac function through binding to muscarinic ACh receptors. Using a rat model of T2DM, our previous studies demonstrated that cell excitability of CVP neurons was reduced in T2DM rats. Given that the rat ICG are divided into the sinoatrial ganglion and atrioventricular ganglion (AVG) and the ventricle only receives projections of vagal nerve terminals from the AVG, our previous study focused on the CVP neurons located in AVG and found that reduced cell excitability of CVP neurons contributed to the withdrawal of ventricular vagal function and ventricular arrhythmogenesis. However, it remains unclear if and how reduced cell excitability of CVP neurons contributes to MI-induced malignant ventricular arrhythmias and high mortality in T2DM. Therefore, we first observed the correlation between CVP neuron excitability and MI-induced ventricular arrhythmias in T2DM rats in Chapter 1. We found that reduced cell excitability of CVP neurons was involved in the withdrawal of ventricular vagal activity, which further aggravated MI-induced ventricular arrhythmias and mortality in T2DM.

Diabetes is a group of metabolic disorders characterized by chronic hyperglycemia, which is accompanied by damage and dysfunction of various tissues and organs. Oxidative stress-induced overproduction of reactive oxygen species (ROS) plays an important role in the pathogenesis of diabetes. Alongside its pathogenetic role in tissue and organs, ROS overproduction also induces neuronal dysfunction in both central and peripheral nervous systems. Our previous study also demonstrated that cell excitability of CVP neurons was reduced due to lower expression of voltage-gated N-type Ca2+ channels in T2DM rats. Considering that hydrogen peroxide (H2O2, the most stable ROS) could acutely modulate various types of voltage-gated Ca2+ channels, it is possible that reduced N-type Ca2+ channel function and cell excitability of CVP neurons might be attributed to ROS overproduction in T2DM. Thus, we tested if and how the elevation of H2O2 inactivates CVP neurons and contributes to cardiac vagal dysfunction in T2DM in Chapter 2. We found that endogenous H2O2 elevation inhibited protein expression and activation of N-type Ca2+ channels and reduced cell excitability of CVP neurons, which further contributed to the withdrawal of cardiac vagal activity and ventricular arrhythmogenesis in T2DM. Additionally, repressor element 1 silencing transcription factor (REST) has been reported to regulate neuronal excitability by repressing excitation-related genes. Since the binding site of the REST was identified in the Cacna1b gene that encodes the α-subunits of N-type Ca2+ channels and ROS donors can induce overexpression of REST in a dose-dependent manner, it is possible that the REST signaling pathway might be involved in ROS-reduced cell excitability of CVP neurons by modulating N-type Ca2+ channel expression in CVP neurons in the T2DM state. Therefore, we further tested whether ROS-elevated REST expression is involved in T2DM-reduced N-type Ca2+ channel expression in CVP neurons in Chapter 3. We found that re-expression of REST reduced neural excitability by inhibiting the expression of the N-type Ca2+ channel in CVP neurons, which subsequently decreased cardiac vagal activity and promoted MI-evoked fatal ventricular arrhythmias in T2DM. Our study for the first time explored the mechanisms responsible for MI-induced ventricular arrhythmias and high mortality in T2DM, which would benefit to development of novel therapeutic interventions for improving prognosis and reducing mortality in patients with T2DM.

Comments

2023 Copyright, the authors

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