ENO1-Related Signaling in Hypertension-Associated Atrial Remodeling: Evidence Implicating PI3K/AKT and NOX4
4 affiliations
- 1Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- 2Center for Cardiac Arrhythmias and Cardiomyopathy (Clinical & Research), Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- 3Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Hangzhou 310016, China
- 4Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Hangzhou 310016, China
Abstract
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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BibTeX
@article{lou2026eno1related,
title = {{ENO1-Related Signaling in Hypertension-Associated Atrial Remodeling: Evidence Implicating PI3K/AKT and NOX4}},
author = {Yang Lou and Qian Zhu and Yuhang Tao and Yameng Chen and Shiquan Chen and Zuwen Zhang and Hongqiang Cheng and Guosheng Fu and Chenyang Jiang},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211970},
url = {https://www.mdpi.com/2073-4409/15/21/1970},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ENO1-Related Signaling in Hypertension-Associated Atrial Remodeling: Evidence Implicating PI3K/AKT and NOX4
AU - Yang Lou
AU - Qian Zhu
AU - Yuhang Tao
AU - Yameng Chen
AU - Shiquan Chen
AU - Zuwen Zhang
AU - Hongqiang Cheng
AU - Guosheng Fu
AU - Chenyang Jiang
PY - 2026
DA - 2026/10/29
JO - Cells
DO - 10.3390/cells15211970
UR - https://www.mdpi.com/2073-4409/15/21/1970
AB - 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.
SN - 2073-4409
ER -