Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

Authors

Xiaolei Wang
Jia Song
Yue Yuan
Luge Li
Issam Abu-Taha
Jordi Heijman
Liang Sun
Shokoufeh Dobrev
Markus Kamler
Liang Xie
Xander H T Wehrens
Frank T Horrigan
Dobromir Dobrev
Na Li

Publication Date

6-23-2023

Journal

Circulation Research

DOI

10.1161/CIRCRESAHA.122.322213

PMID

37154033

PMCID

PMC10330339

PubMedCentral® Posted Date

6-23-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Mice, Animals, Atrial Fibrillation, Down-Regulation, Myocytes, Cardiac, Hypoxia, Heat-Shock Proteins

Abstract

BACKGROUND: Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of

METHODS: Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding

RESULTS: FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent (chronic) AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca

CONCLUSIONS: This is the first study to demonstrate a role for the FKBP5-deficiency in atrial arrhythmogenesis and to establish FKBP5 as a negative regulator of hypoxia-inducible factor 1α in cardiomyocytes. Our results identify a potential molecular mechanism for the proarrhythmic NCX1 upregulation in chronic AF patients.