Key result
Pharmacologic SK3 activation attenuates progressive LMNA-mediated AV block in preclinical models.
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Why the study?
LMNA mutations have been linked to atrioventricular block in patients, but the underlying mechanisms remain largely unclear.
LMNA deficiency causes atrioventricular block partly through downregulation of SK3 channels, and pharmacologic activation of SK3 presents a potential novel therapeutic target.
BACKGROUND Atrioventricular block (AVB) is a conduction system disorder that, when severe, results in pacemaker implantation. LMNA mutations affecting the nuclear envelope proteins lamin A/C have been linked to AVB in patients, yet the underlying mechanisms remain largely unclear. The authors identified a nonsense LMNA-R225X mutation in a kindred that was associated with progressive AVB and atrial arrhythmias, followed by left ventricular dysfunction. OBJECTIVES The aims of this study were to elucidate the mechanisms underlying LMNA-R225X-mediated AVB and to identify novel therapeutic targets for its treatment. METHODS LMNA-R225X-knock-in mice were generated using clustered regularly interspaced short palindromic repeats/Cas9 technology. Cardiac phenotype was characterized using surface electrocardiography, telemetry electrocardiography, programmed electrical stimulation, and echocardiography. Histology, immunofluorescence staining, Ca2+ imaging, and RNA sequencing were performed to elucidate the mechanistic underpinnings of AVB. RESULTS Homozygous LMNA-R225X mice displayed bradycardia and first-degree AVB before death at 2 weeks. Similar to patients, R225X-heterozygous mice exhibited age-dependent progressive AVB, ranging from first to second degree, and increased susceptibility to atrial fibrillation, preceding the development of cardiomyopathy. Specific knockdown of LMNA in cardiac conduction system pacemaker cells was sufficient to induce AVB. RNA sequencing analysis of atrioventricular node tissue revealed up-regulation of genes related to fibrosis and cellular hypertrophy, accompanied by down-regulation of the small-conductance calcium-activated potassium channel type 3 (SK3) channel. Ca2+ imaging further demonstrated impaired automaticity of R225X-heterozygous atrioventricular node pacemaker cells. Pharmacologic activation of SK3 channel attenuated AVB in both LMNA deficiency models. CONCLUSIONS These findings establish a direct role of LMNA deficiency in AVB and reveal the SK3 channel as a therapeutic target for the management of AVB.
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Li et al. (2026) studied Atrioventricular block. LMNA deficiency (LMNA-R225X mutation) was evaluated on Development of atrioventricular block and electrophysiological mechanisms. LMNA deficiency causes progressive atrioventricular block via SK3 channel down-regulation, which can be attenuated by pharmacologic SK3 activation in preclinical models.
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