The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency

Kyungsoo Kim, Daniel J. Blackwell, Samantha L. Yuen, Madelaine P. Thorpe, Jeffrey N. Johnston, Razvan L. Cornea, Björn C. Knollmann

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and morbidity. The strongest genetic risk factors for AF in humans are variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene PITX2. Although mice deficient in Pitx2 (Pitx2+/−) have increased AF susceptibility, the mechanism remains controversial. Recent evidence has implicated hyperactivation of the cardiac ryanodine receptor (RyR2) in Pitx2 deficiency, which may be associated with AF susceptibility. We investigated pacing-induced AF susceptibility and spontaneous Ca2+ release events in Pitx2 haploinsufficient (+/−) mice and isolated atrial myocytes to test the hypothesis that hyperactivity of RyR2 increases susceptibility to AF, which can be prevented by a potent and selective RyR2 channel inhibitor, ent-verticilide. Compared with littermate wild-type Pitx2+/+, the frequency of Ca2+ sparks and spontaneous Ca2+ release events increased in permeabilized and intact atrial myocytes from Pitx2+/− mice. Atrial burst pacing consistently increased the incidence and duration of AF in Pitx2+/− mice. The RyR2 inhibitor ent-verticilide significantly reduced the frequency of spontaneous Ca2+ release in intact atrial myocytes and attenuated AF susceptibility with reduced AF incidence and duration. Our data demonstrate that RyR2 hyperactivity enhances SR Ca2+ leak and AF inducibility in Pitx2+/− mice via abnormal Ca2+ handling. Therapeutic targeting of hyperactive RyR2 in AF using ent-verticilide may be a viable mechanism-based approach to treat atrial arrhythmias caused by Pitx2 deficiency.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume180
DOIs
StatePublished - Jul 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Ltd

Keywords

  • Atrial fibrillation
  • Calcium
  • Cardiac ryanodine receptor (RyR2)
  • Pitx2
  • ent-Verticilide

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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