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Propionylation at OXCT1 lysine-296 is the key mechanism of atrial fibrillation in both patients and atrial-specific knockout of the LKB1 mouse model

ABSTRACT: Atrial fibrillation (AF), the most prevalent clinical arrhythmia, imposes a major global health burden through elevated risks of stroke, heart failure, and mortality. Lysine propionylation (Kpr) is mainly involved in metabolic regulation and plays an important role in cardiac pathophysiology. However, the specific role and mechanism of Kpr in AF remain unclear. Here we show that significantly increased Kpr levels of 3-oxoacid CoA-transferase 1 (OXCT1) at lysine-296 (K296) were found both in atrial tissues of AF mice induced by atrial-specific LKB1 knockout and in right atrial tissues of patients with postoperative AF (POAF) after coronary artery bypass grafting (CABG). We found that propionylation greatly reduced the enzyme activity of OXCT1 and inhibited its interaction with acetyl-CoA acetyltransferase 1 (ACAT1), leading to decreased ACAT1 protein expression. Furthermore, on the one hand, these changes reduced the production of succinate and adenosine triphosphate (ATP), resulting in an imbalance of mitochondrial energy metabolism, and on the other hand, increased the production of intracellular ROS and mitochondrial ROS (mitoROS), triggering oxidative stress. Our results reveal that elevated propionylation of OXCT1 at K296 is a crucial molecular mechanism underlying AF, providing new insights into the etiology of AF and potential therapeutic targets.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Hai-Tao Hou

LAB HEAD: HOU HT

PROVIDER: PXD067998 | Pride | 2026-08-07

REPOSITORIES: Pride

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Source:

			Action	DRS
	Results.zip	Other
	XA07863DPPr_LKB1_KO1_Slot1-11_1_1214.d.zip	Other
	XA07863DPPr_LKB1_KO2_Slot1-11_1_1216.d.zip	Other
	XA07863DPPr_LKB1_KO3_Slot1-11_1_1218.d.zip	Other
	XA07863DPPr_LKB1_WT1_Slot1-10_1_1208.d.zip	Other

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Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation

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Propionylation at OXCT1 lysine-296 is the key mechanism of atrial fibrillation in both patients and atrial-specific knockout of the LKB1 mouse model

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