Poster abstracts

Poster number 60 submitted by Jingru Liang

Lipokine 12,13-diHOME Protects Against Obesity-Associated Atrial Fibrillation by Attenuation of CaMKII

Jingru Liang (Molecular, Cellular, and Developmental Biology Graduate Program), Benjamin Buck, Shinsuke Nirengi, Xianyao Xu, Natasha M. James (Department of Surgery, Dorothy M. Davis Heart and Lung Research Institute), Elizabeth Luczak (School of Medicine, Johns Hopkins University ), Lisa Baer, Daniel Gallego-Perez, Thomas Hund and Kristin Stanford

Abstract:
Atrial fibrillation (AF) is the most common cardiac arrhythmia and a leading cause of stroke and heart failure (1). Obesity is a major risk factor for AF, and metabolic mediators are increasingly implicated in its pathogenesis (2). We recently identified 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), a linoleic acid-derived lipokine and novel cardiometabolic regulator (3). Circulating 12,13-diHOME is reduced in individuals with obesity or AF and improves cardiac function in mice, suggesting a protective role in obesity-associated AF (4). Calcium/calmodulin-dependent protein kinase II (CaMKII), a key driver of AF (5), is upregulated in obese hearts, and impaired CaMKII signaling reduces AF susceptibility under high-fat diet (HFD) conditions (6). We previously demonstrated that 12,13-diHOME directly binds to and inhibits CaMKII (7). Here, we tested whether 12,13-diHOME attenuates obesity-associated AF via CaMKII inhibition. In diet-induced obese mice, intracardiac pacing showed that acute 12,13-diHOME administration reduced AF inducibility in both sexes. Sustained overexpression of 12,13-diHOME using tissue nanotransfection (TNT-Ephx1/2) similarly decreased AF susceptibility in female. In isolated atrial myocytes, HFD prolonged action potential duration and increased spontaneous depolarizations, effects reversed by 12,13-diHOME. Mechanistically, 12,13-diHOME suppressed pacing-induced CaMKII activation in neonatal rat ventricular myocytes and reduced cardiac phosphorylated CaMKII in HFD-TNT-Ephx1/2 mice. These findings demonstrate that 12,13-diHOME protects against obesity-associated AF by attenuating CaMKII signaling, highlighting its therapeutic potential in metabolic heart diseases.

References:
1. Card Electrophysiol Clin 13, 243-255 (2021).
2. Cardiovasc Diabetol 22, 192 (2023).
3. Circulation 143, 145-159 (2021).
4. Circ Arrhythm Electrophysiol 17, e012486 (2024).
5. Heart Rhythm 17, 503-511 (2020).
6. Int J Obes (Lond) 45, 795-807 (2021).
7. Nat Commun 16, 7088 (2025).

Keywords: Lipokine , obesity , atrial fibrillation