Life sciences · 2026
Orai3 deficiency drives atrial remodeling and fibrillation susceptibility via Orai channel remodeling and SOCE hyperactivation.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Wu Xiaohe, Xue Yangcheng, Lu Haoyang, Cao Yanlong, Li Danni, Liang Ao, Zheng Peiyang, Zhang Ran, Jia Zhuoran, Zhao Ren
Аннотация
AIMS: Atrial remodeling is the pathological substrate for atrial fibrillation (AF), yet no targeted therapies exist. The Orai3 calcium channel regulates cardiac homeostasis, but its role in atrial remodeling remains unexplored.
METHODS: Wild type and Orai3 knockout rats were subjected to Angiotensin II infusion or acetylcholine‑calcium chloride injection to model atrial fibrosis and AF. Cardiac function, Orai channel related protein expression and co-localization, SOCE activity, and downstream signaling were evaluated by echocardiography, histology, immunofluorescence, calcium imaging, and western blotting.
RESULTS: Orai3 deficiency exacerbated Ang II induced atrial dilation, fibrosis, and ultrastructural damage, with transcriptomic analysis revealing enrichment of extracellular matrix pathways. Mechanistically, Orai3 loss was associated with reduced Orai1/Orai3 co-localization and enhanced Orai1/STIM1 co-localization, driving SOCE hyperactivation. This aberrant Ca2+ signal bidirectionally upregulated TGF-β and suppressed Cx43 effects reversible by SOCE inhibition or Orai3 overexpression. Orai3 has been proposed to function as a molecular rheostat that down tunes STIM1 mediated gating when in complex with Orai1, its loss removes this brake, unleashing pathological SOCE. Consequently, Orai3 deficient rats exhibited increased AF susceptibility, with disrupted Cx43 distribution, shortened gap junctions, and impaired STAT3 mediated Cx43 transcription.
CONCLUSIONS: Orai3 acts as an endogenous protective brake against atrial cardiomyopathy. The Orai3-SOCE-TGF-β/Cx43 axis links calcium dyshomeostasis to both fibrotic and electrical remodeling, positioning Orai3 as a potential prognostic biomarker and therapeutic target for AF.
METHODS: Wild type and Orai3 knockout rats were subjected to Angiotensin II infusion or acetylcholine‑calcium chloride injection to model atrial fibrosis and AF. Cardiac function, Orai channel related protein expression and co-localization, SOCE activity, and downstream signaling were evaluated by echocardiography, histology, immunofluorescence, calcium imaging, and western blotting.
RESULTS: Orai3 deficiency exacerbated Ang II induced atrial dilation, fibrosis, and ultrastructural damage, with transcriptomic analysis revealing enrichment of extracellular matrix pathways. Mechanistically, Orai3 loss was associated with reduced Orai1/Orai3 co-localization and enhanced Orai1/STIM1 co-localization, driving SOCE hyperactivation. This aberrant Ca2+ signal bidirectionally upregulated TGF-β and suppressed Cx43 effects reversible by SOCE inhibition or Orai3 overexpression. Orai3 has been proposed to function as a molecular rheostat that down tunes STIM1 mediated gating when in complex with Orai1, its loss removes this brake, unleashing pathological SOCE. Consequently, Orai3 deficient rats exhibited increased AF susceptibility, with disrupted Cx43 distribution, shortened gap junctions, and impaired STAT3 mediated Cx43 transcription.
CONCLUSIONS: Orai3 acts as an endogenous protective brake against atrial cardiomyopathy. The Orai3-SOCE-TGF-β/Cx43 axis links calcium dyshomeostasis to both fibrotic and electrical remodeling, positioning Orai3 as a potential prognostic biomarker and therapeutic target for AF.