Key result
ENO1 inhibition attenuates atrial remodeling and shortens pacing-induced AF duration in hypertensive mice.
Why the study?
Hypertension is a major risk factor contributing to the initiation and maintenance of AF, and this study investigated the contribution of enolase 1 (ENO1) and PI3K/AKT and NOX4 signaling to hypertension-associated atrial remodeling and susceptibility to pacing-induced AF.
Does ENO1 inhibition or knockdown attenuate hypertension-associated atrial remodeling and pacing-induced atrial fibrillation susceptibility in preclinical rodent and cellular models?
Does ENO1 inhibition or knockdown attenuate hypertension-associated atrial remodeling and pacing-induced atrial fibrillation susceptibility in preclinical rodent and cellular models?
This preclinical study demonstrates that ENO1 regulates NOX4 via PI3K/AKT signaling to promote hypertension-associated atrial remodeling, and its pharmacological inhibition with AP-III-a4 attenuates atrial fibrosis and shortens pacing-induced AF duration in mice.
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia worldwide; hypertension is one of the most important risk factors for AF and contributes to both its initiation and maintenance. This study investigated the contribution of enolase 1 (ENO1) to hypertension-associated atrial remodeling and susceptibility to pacing-induced AF. Long-term hypertension was associated with increased AF inducibility in rats, and atrial transcriptomic analyses at two stages of hypertension identified persistent ENO1 upregulation. ENO1 was also increased in two external human left atrial AF datasets. An angiotensin II (Ang II)-induced atrial cardiomyocyte injury model was constructed to evaluate the role of ENO1 in Ang II-induced cardiomyocyte hypertrophy. In Ang II-stimulated primary neonatal rat atrial cardiomyocytes, siRNA-mediated ENO1 knockdown attenuated hypertrophic and oxidative-stress-related changes and was accompanied by lower PI3K/AKT phosphorylation and NADPH oxidase 4 (NOX4) expression. AP-III-a4 treatment produced concordant changes in selected cellular endpoints. PI3K inhibition reduced NOX4 expression and intracellular hydrogen peroxide levels. In ENO1-silenced cardiomyocytes, PI3K activation with 740Y-P partially increased both PI3K/AKT phosphorylation and NOX4 expression. In Ang II-infused hypertensive mice, AP-III-a4 treatment reduced atrial enlargement, fibrosis, PI3K/AKT phosphorylation, NOX4 expression, and atrial reactive oxygen species signals; it also attenuated atrial effective refractory period shortening. AP-III-a4 significantly shortened the duration of pacing-induced AF and was associated with numerically lower AF inducibility, although the latter difference did not reach statistical significance. Collectively, these findings support the involvement of PI3K/AKT signaling in ENO1-associated regulation of NOX4 and suggest that this relationship may contribute to the observed attenuation of hypertension-associated atrial remodeling.
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Lou et al. (2026) studied Hypertension-associated atrial remodeling and atrial fibrillation. ENO1 knockdown (siRNA) and AP-III-a4 (ENO1 inhibitor) vs. Untreated or control Ang II-stimulated cells and hypertensive mice; PI3K activation with 740Y-P in rescue experiments was evaluated on Atrial remodeling (enlargement, fibrosis, oxidative stress, PI3K/AKT/NOX4 signaling) and pacing-induced AF duration and inducibility. AP-III-a4 and ENO1 knockdown attenuated Ang II-induced atrial remodeling, PI3K/AKT/NOX4 signaling, and significantly shortened pacing-induced AF duration in hypertensive mice.
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