Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Marco A. M. Prado

2nd Supervisor

Dr. Robert Gros

Joint Supervisor

Abstract

­Cardiac remodeling and dysfunction occur prior to the onset of heart failure. Altered regulation of cardiac function by the autonomic nervous system has been implicated in the progression of heart disease. Both altered sympathetic and parasympathetic tone contribute to cardiac disease; however, the role of the parasympathetic nervous system, and specifically acetylcholine (ACh), in cardiac dysfunction has not been fully elucidated. In these studies, we sought to determine whether changes in neuronal and/or non-neuronal ACh release regulate cardiac activity and alter the progression of cardiac remodeling and dysfunction. A systemic decrease in the expression of the vesicular acetylcholine transporter (VAChT), the protein responsible for packaging ACh, led to the development of significant ventricular dysfunction coupled with significant transcriptional changes in cardiac tissue. Furthermore, we identified that murine cardiomyocytes possess an intrinsic cholinergic system, which prevents hypertrophy and molecular remodeling in cardiomyocytes in response to hyperadrenergic stimulation, in vitro. In addition, this cardiac non-neuronal cholinergic system (NNCS) is also critical in regulating heart activity and remodeling, in vivo. Inhibition of cardiomyocyte-specific ACh secretion led to delayed heart rate recovery following physiological stress, including exercise, as well as significant ventricular remodeling. Cardiomyocytes lacking the intrinsic cholinergic system displayed hypertrophy and molecular remodeling. This NNCS also plays a significant role under pathological conditions as chronic treatment with angiotensin II led to enhanced cardiac remodeling and ventricular dysfunction in mice lacking the NNCS. Additionally, this intrinsic cholinergic system in the heart is also present in human cardiomyocytes, suggesting the conserved expression of prototypic markers of the cholinergic system in man. This system might be of functional significance in cardiac disease as failing human cardiomyocytes exhibit increased VAChT expression, which likely leads to an increase in ACh secretion directly from cardiomyocytes. The increase in VAChT expression may play a protective role in heart failure, as overexpression of VAChT in mice did not reveal adverse phenotypes under physiological conditions. Our data suggest that both neuronal and non-neuronal ACh are critical in maintaining cardiac homeostasis and deficient cholinergic signaling contributes to ventricular remodeling and cardiac dysfunction.

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