Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Sami Noujaim, Ph.D.

Committee Member

Craig Doupnik, Ph.D.

Committee Member

Jerome Breslin, Ph.D.

Committee Member

Javier Cuevas, Ph.D.

Committee Member

Crystal Ripplinger, Ph.D.

Keywords

AF, Aging, PKCɛ, IKACh

Abstract

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias seen in the clinics, and currently available antiarrhythmic pharmacotherapies in AF are not very effective. Although AF has been recognized as an aging-mediated disease, our understanding of the electrophysiological pathways that link aging and AF remain incomplete, which limits breakthroughs in the development of novel antiarrhythmic treatments for this disease. Studies have shown that aging increases the generation of reactive oxygen species (ROS) in the heart, and high levels of ROS have been associated with development of AF in animals and patients. Additionally, in some forms of AF, the acetylcholine activated inwardly rectifying potassium current (IKACh) is constitutively active, possibly in a protein kinase C epsilon (PKCε) dependent manner. However, at present, there are no direct and fundamental mechanistic links between aging, constitutively active IKACh, and AF. In this thesis, I will utilize a PKCε knock out mouse, molecular, electrophysiological and protein engineering approaches to test the hypothesis that in the heart, aging leads to constitutively active IKACh via PKCε, and thus to the perpetuation of AF. My results demonstrate that the increased susceptibility for AF in the aging heart is in part dependent on a PKCε mediated constitutively active IKACh and that blocking IKACh with a novel and highly potent blocker that we designed reduces the susceptibility to AF in the aging heart. It is my sincere hope that the work I present in this thesis could provide insights into the molecular underpinnings of a novel xii pathway that contributes to the atrial arrhythmogenicity of aging. I also hope that my work would open new avenues for the design of novel ion channels blocking modalities that can be used as a new generation of effective antiarrhythmics.

Download

Included in

Physiology Commons

Share

COinS