Basic/Translational Science -> Intact Heart Electrophysiology (includes Pharmacology and Optical Mapping) D-PO01 - Featured Poster Session (ID 11) Poster

D-PO01-212 - Pkc Epsilon Contributes To The Mechanisms Of Atrial Fibrillation In Aging (ID 969)

Disclosure
 M. Chang: Nothing relevant to disclose.

Abstract

Background: Atrial fibrillation (AF) is recognized as a disease of aging. However, the mechanisms of aging mediated AF are not well understood. Reactive oxygen species have been shown to be higher in the aging heart and IKAch (acetylcholine activated inward rectifier potassium current) is constitutively active in patient with chronic AF, in a protein kinase C epsilon (PKCe) dependent manner.
Objective: We investigated the role of PKCe in aging mediated AF. We hypothesized that PKCe plays a role in aging related AF via oxidative stress mediated activation of IKAch and via structural remodeling. We used aged PKCe knock out (KO) and wild type littermate mice to conduct our animal experiments.
Methods: RNA seq was performed on 3 WT and 3 KO old mouse atrial samples for transcriptomics analysis using the Illumina NextSeq-550 platform. HL-1 atrial myocytes were used for co-immunoprecipitation and western blots. We also conducted intracardiac programmed electrical stimulation in WT (n=15, age: 17±3 months) and KO (n=13, age: 17±3 months) old mice using an octapolar catheter. AF inducibility and duration were analyzed before and after jugular vein injection of tertiapinQ (5uM, 50ul).
Results: RNA seq showed that genes for extracellular matrix and protein oxidation pathways were differentially regulated in old WT vs old KO atria. Moreover, in HL-1 myocytes, oxidative stress activated PKCe, causing its translocation from the cytosol to the cell membrane. Additionally, PKCe, Kir3.1, and Kir3.4 (the molecular correlates of IKAch) and caveolin 3 co-immunoprecipitated. In WT mice, AF was more inducible than in KO mice (80% compared to 38%, p<0.05). AF duration in WT mice (10.03 seconds) was longer compared to KO animals (6.37 seconds), p= 0.013. In a subset of 8 WT mice, TertiapinQ reduced AF inducibility from 87 % to 0%. In 7 KO mice, AF inducibility was 28% before tertiapinQ to 14% after tertiapinQ, suggesting that IKAch is constitutively active in the aged WT atria, but not in KO.
Conclusion: PKCe knock out reduces the inducibility of AF in old mice through a possible abrogation of oxidative stress mediated IKAch constitutive activity, and through possible remodeling of the extracellular matrix.
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