Publication Date

2019-12-09

Availability

Open access

Embargo Period

2019-12-09

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Physiology and Biophysics (Medicine)

Date of Defense

2019-10-14

First Committee Member

Hans Peter Larsson

Second Committee Member

Laura Bianchi

Third Committee Member

Lynne A. Fieber

Fourth Committee Member

Kevin M. Collins

Fifth Committee Member

Scott B. Hansen

Abstract

Cardiac arrhythmia leads to 325,000 cases of sudden cardiac death annually in adults alone (Clinic 2017). Long QT Syndrome (LQTS) is an arrhythmogenic disorder that is caused by mutations (or channelopathies) in voltage-gated ion channels expressed in the cardiomyocyte. Polyunsaturated fatty acids (PUFAs) have emerged as a potential therapeutic for the treatment of LQTS because they modulate the activity of voltage-gated ion channels involved in LQTS pathology. PUFAs are amphipathic molecules with a hydrophilic head group, as well as long, polyunsaturated hydrophobic tail. In this work, we demonstrate that the position of the double bonds in the hydrophobic tail influence the apparent binding affinity of the PUFA to the cardiac Kv7.1/KCNE1 channel complex. We also find that alterations to the hydrophilic head group (i.e. substituting a carboxyl head for a glycine or taurine group) result in a range of Kv7.1/KCNE1 channel activators. Lastly, we find that PUFAs range in their selectivity for different voltage-gated channels expressed in the heart (e.g. Nav1.5, Cav1.2, and Kv7.1/KCNE1). Specifically, PUFA analogues with taurine head groups tend to have broad effects on multiple voltage-gated ion channels including Nav1.5, Cav1.2, and Kv7.1/KCNE1. However, PUFA analogues with glycine head groups tend to have more selective effects on Kv7.1/KCNE1 channels. PUFA analogues with glycine head groups such as pinoleoyl glycine and DHA-glycine are able to partially restore a prolonged ventricular action potential and prevent arrhythmia in simulated cardiomyocytes. These results suggest a therapeutic role of polyunsaturated fatty acid analogues in the treatment of cardiac arrhythmia.

Keywords

IKs; Kv7.1; Cav1.2; Nav1.5; cardiac arrhythmia; Long QT Syndrome; polyunsaturated fatty acids

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