TY - JOUR
T1 - Rapamycin attenuates age-related atrial remodeling and fibrillation by targeting HIF-1α-mediated metabolic dysregulation
AU - Jin, Lingyan
AU - Jiang, Tiannan
AU - Gong, Haoyu
AU - Gong, Lulu
AU - Wang, Yizhen
AU - Chen, Ziwei
AU - Liu, Peng
AU - Qin, Xinghua
AU - Zheng, Qiangsun
N1 - Publisher Copyright:
© 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
PY - 2027/1
Y1 - 2027/1
N2 - Background: Atrial fibrillation (AF) is an age-related disease associated with substantial morbidity and mortality. Although rapamycin stands as a foremost anti-aging therapy with proven efficacy in lifespan extension, a critical gap exists in understanding its impact on aging-induced atrial remodeling and AF susceptibility. Objective: This study aims to evaluate the therapeutic potential of rapamycin against aging-related AF and elucidate its underlying mechanisms. Methods: An aging-induced AF-susceptible mouse model was induced by D-galactose injection, followed by rapamycin diet. Subsequent evaluations included AF susceptibility, atrial electrical/structural remodeling, and mechanistic analyses. Results: Rapamycin significantly reduced aging-induced AF susceptibility. It also ameliorated atrial electrical and structural remodeling. Metabolically, it improved systemic insulin resistance, restored mitochondrial function and morphology, and counteracted aging-induced perturbations in substrate utilization. Mechanistically, rapamycin inhibited hypoxia inducible factor-1α (HIF-1α) transcriptional activity, a key metabolic target in the aging process. Cellular experiments confirmed that rapamycin directly suppressed CoCl₂-induced HIF-1α expression and nuclear translocation, and pharmacological restoration of HIF-1α effectively attenuates the protective effects of rapamycin against D-galactose-induced atrial structural remodeling. Furthermore, molecular docking, dynamics simulations and isothermal titration calorimetry (ITC) suggested that rapamycin may also directly interfere with HIF-1α dimerization. Importantly, restoration of mTOR activity failed to reverse rapamycin-mediated HIF-1α inhibition, suggesting an mTOR-independent regulatory mechanism. Conclusion: Our findings demonstrate that rapamycin mitigates aging-induced atrial remodeling and AF susceptibility in mice, primarily through the inhibition of HIF-1α and the amelioration of downstream metabolic dysregulation.
AB - Background: Atrial fibrillation (AF) is an age-related disease associated with substantial morbidity and mortality. Although rapamycin stands as a foremost anti-aging therapy with proven efficacy in lifespan extension, a critical gap exists in understanding its impact on aging-induced atrial remodeling and AF susceptibility. Objective: This study aims to evaluate the therapeutic potential of rapamycin against aging-related AF and elucidate its underlying mechanisms. Methods: An aging-induced AF-susceptible mouse model was induced by D-galactose injection, followed by rapamycin diet. Subsequent evaluations included AF susceptibility, atrial electrical/structural remodeling, and mechanistic analyses. Results: Rapamycin significantly reduced aging-induced AF susceptibility. It also ameliorated atrial electrical and structural remodeling. Metabolically, it improved systemic insulin resistance, restored mitochondrial function and morphology, and counteracted aging-induced perturbations in substrate utilization. Mechanistically, rapamycin inhibited hypoxia inducible factor-1α (HIF-1α) transcriptional activity, a key metabolic target in the aging process. Cellular experiments confirmed that rapamycin directly suppressed CoCl₂-induced HIF-1α expression and nuclear translocation, and pharmacological restoration of HIF-1α effectively attenuates the protective effects of rapamycin against D-galactose-induced atrial structural remodeling. Furthermore, molecular docking, dynamics simulations and isothermal titration calorimetry (ITC) suggested that rapamycin may also directly interfere with HIF-1α dimerization. Importantly, restoration of mTOR activity failed to reverse rapamycin-mediated HIF-1α inhibition, suggesting an mTOR-independent regulatory mechanism. Conclusion: Our findings demonstrate that rapamycin mitigates aging-induced atrial remodeling and AF susceptibility in mice, primarily through the inhibition of HIF-1α and the amelioration of downstream metabolic dysregulation.
KW - Aging
KW - Atrial fibrillation
KW - Hypoxia inducible factor-1α
KW - Metabolism
KW - Rapamycin
UR - https://www.scopus.com/pages/publications/105048923989
U2 - 10.1016/j.bbadis.2026.168438
DO - 10.1016/j.bbadis.2026.168438
M3 - 文章
C2 - 42648451
AN - SCOPUS:105048923989
SN - 0925-4439
VL - 1873
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 1
M1 - 168438
ER -