2. Academic Validation
  3. Rab26 promotes hypoxia-induced hyperproliferation of PASMCs by modulating the AT1R-STAT3-YAP axis

Rab26 promotes hypoxia-induced hyperproliferation of PASMCs by modulating the AT1R-STAT3-YAP axis

  • Cell Mol Life Sci. 2025 Nov 13;82(1):396. doi: 10.1007/s00018-025-05923-2.
Zaichun You # 1,  Qiuhong Huang # 1,  Li Zeng # 1,  Xin Tian 1,  Wen Zhang 2,  Dongqin Wei 1,  Juan Fu 1,  Liling Xu 1,  Li Ren 1,  Yan Zhao 1,  Hang Qian 2,  Guansong Wang 3 4,  Xunmei Zhou 5,  Binfeng He 6 7
Affiliations

Affiliations

  • 1 Department of General Practice, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University (Army Medical University), Institute of Respiratory Diseases, Chongqing, 400037, China.
  • 3 Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University (Army Medical University), Institute of Respiratory Diseases, Chongqing, 400037, China. wanggs@tmmu.edu.cn.
  • 4 Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China. wanggs@tmmu.edu.cn.
  • 5 Department of General Practice, University-Town Hospital Chongqing Medical University, Chongqing, 400030, China. xunmei_zhou@hospital.cqmu.edu.cn.
  • 6 Department of General Practice, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China. ldhbf@tmmu.edu.cn.
  • 7 Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China. ldhbf@tmmu.edu.cn.
  • # Contributed equally.
PMID: 41231254 DOI: 10.1007/s00018-025-05923-2
Abstract

The hyper-proliferation of pulmonary artery smooth muscle cells (PASMCs) significantly contributes to pulmonary vascular remodeling (PVR) in chronic hypoxic pulmonary arterial hypertension (PAH), leading to right ventricular dysfunction and increased mortality. Despite the critical role of this process, the mechanisms underlying hypoxia-induced PASMCs hyper-proliferation remain largely unexplored. In this study, hypoxia was found to upregulate Rab26 expression in rat PASMCs (rPASMCs) and lung tissue in a PAH mouse model. Silencing Rab26 reduced rPASMCs hyper-proliferation. Rab26 interacted with angiotensin II Type 1 receptor (AT1R) and modulated its transport to the cell surface, thereby activating Signal Transducer and Activator of Transcription 3 (STAT3), upregulating Yes-associated protein 1 (YAP1) expression, and promoting YAP1 nuclear translocation. Moreover, hypoxia enhanced the interaction between YAP and STAT3, with STAT3 also facilitating YAP nuclear translocation. Rab26 deficiency downregulates the levels of pSTAT3 and YAP1 in lung tissue and smooth muscle arteries and attenuated the hypoxia-induced PVR. Rab26 deficiency results in decreased expression of pSTAT3 and YAP1 in lung tissue and pulmonary smooth muscle arteries, while also attenuating hypoxia-induced PVR. Furthermore, pharmacological inhibition of AT1R and pSTAT3 further reduces pSTAT3 and YAP1 expression both in wild-type (WT) and Rab26-/- PAH mice. In summary, our findings demonstrate that Rab26 facilitates PASMC hyper-proliferation and pulmonary vascular remodeling by modulating AT1R transport and activating the downstream STAT3-YAP pathway under hypoxic conditions. These results suggest that targeting Rab26 may be a promising therapeutic strategy for PVR and PAH.

Keywords

AT1R; PVR; Rab26; STAT3; YAP1.

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