In clinical practice, atrial fibrillation (AF) is the most common heart rhythm disturbance, and a major cause of morbidity and mortality. The incidence of AF increases greatly with age, and given the aging of our overall population, its prevalence is rising at alarming rates. Yet the treatment of AF remains inadequate due in part to our relatively poor understanding of AF pathoelectrophysiology. In this application, we propose to focus on aging mediated AF. The goal is to investigate previously unexplored direct mechanistic links between aging, oxidative stress, the acetylcholine sensitive inward rectifier potassium current IKACh, and AF. We will test the hypothesis that the increased oxidative stress in aged atria activates PKCepsilon, which in turn phosphorylates Kir3.1- a molecular correlate of IKACh, leading to muscarinic stimulation independent constitutively active IKACh, shortening of action potential duration, and AF perpetuation. Our preliminary data support our hypothesis and show that: 1-) aging promotes the phosphorylation of Kir3.1 and leads to the constitutive activation of IKACh, 2-) oxidative stress activates PKCepsilon, phosphorylates Kir3.1, and shortens the atrial action potential due to a constitutively active IKACh, and facilitates the development of rotors responsible for AF, and 3)- phosphorylation of Kir3.1 initiates conformational changes which could increase the channel's interaction with its activator PIP2, and result in the opening of the channel's intracellular ion permeation pathway. We will test our hypothesis in 3 specific aims: 1-) To investigate the molecular and signaling pathways leading to constitutively active IKACh in aging, through oxidative stress and PKCepsilon mediated Kir3.1 phosphorylation; 2-) To determine the structural changes that occur in Kir3.1 phosphorylated by PKCepsilon, with X-ray crystallography and molecular dynamics simulations; and 3-) To study the role of aging, PKCepsilon and constitutively active IKACh in the inducibility and dynamics of atrial fibrillation. We will make simultaneous use of several complementary and powerful techniques (X-ray crystallography, molecular modeling, molecular biology, single cell, and whole organ electrophysiology) to test our aims and to investigate from the protein structure, to the multicellular level, the details of how aging modifies the structure and function of an ion channel, leading to proarrhythmic electrical changes in the atria. We postulate that the studies proposed will increase our understanding of AF pathoelectrophysiology, and could direct the identification of antifibrillatory pathway targets, and the development of novel, specific, and effective anti-atrial fibrillation agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL129136-02
Application #
9201766
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2015-07-01
Project End
2020-04-30
Budget Start
2016-04-15
Budget End
2017-04-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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