2. Academic Validation
  3. The transcription factor RBPJ is required for inflammatory macrophage activation in thoracic aortic dissection by mediating mechanotransduction-induced glycolysis

The transcription factor RBPJ is required for inflammatory macrophage activation in thoracic aortic dissection by mediating mechanotransduction-induced glycolysis

  • Cell Mol Life Sci. 2025 Oct 28;82(1):370. doi: 10.1007/s00018-025-05908-1.
Zhi-Qiang Yin # 1 2,  Ting Wen # 2,  Xiu-Li Cao # 2,  Zhao-Xia Lv 2 3,  Yang Su 2,  Liang Liang 2,  Pei-Ran Zhang 2,  Zi-Yan Yang 2,  Hua Han 4,  Xian-Chun Yan 5,  Qi-Jun Zheng 6
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, Shenzhen People's Hospital, Second Clinical Medical School, the First Affiliated Hospital, Jinan University, Southern University of Science and Technology, Shenzhen, 518020, China.
  • 2 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an, 710032, China.
  • 3 Department of Pediatrics, Bethune International Peace Hospital, Shijiazhuang, 050082, China.
  • 4 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an, 710032, China. huahan@fmmu.edu.cn.
  • 5 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an, 710032, China. yanxianchun@fmmu.edu.cn.
  • 6 Department of Cardiovascular Surgery, Shenzhen People's Hospital, Second Clinical Medical School, the First Affiliated Hospital, Jinan University, Southern University of Science and Technology, Shenzhen, 518020, China. zhengqj@szhospital.com.
  • # Contributed equally.
PMID: 41148245 DOI: 10.1007/s00018-025-05908-1
Abstract

Abnormal infiltration and activation of monocyte-derived macrophages (moMFs) contribute significantly to thoracic aortic dissection (TAD). The transcription factor RBPJ mediates canonical Notch signaling and modulates macrophage activation, but the role and mechanism of RBPJ in macrophages in TAD remains unclear. Here, we show that RBPJ was upregulated in macrophages infiltrating the aorta in TAD patients and BAPN-induced mouse model. Myeloid-specific Rbpj ablation protected mice from TAD, reducing death, aortic damage, macrophage infiltration, and M1-like polarization while enhancing M2-like polarization. Because moMFs dominate aorta as shown in public scRNA-seq data, and RBPJ is upregulated in moMFs compared with blood monocytes/macrophages, we assumed that mechanical force, specifically cyclic stretch, might be one of the environmental cues of macrophage activation in aorta. Indeed, bone marrow-derived macrophages (BMDMs) loaded with cyclic stretch upregulated RBPJ expression in a Piezo1-dependent way, accompanied by increased M1-like polarization, and Rbpj ablation cancelled the force-induced M1-like polarization. By RNA-sequencing, we found that cyclic stretch induced a metabolic reprogram of BMDMs characterized by upregulation of glycolysis-related genes and HIF1α, which was dependent on RBPJ. Further analyses showed that cyclic stretch upregulated PDK1, a negative regulator of pyruvate dehydrogenase (PDH), which was abrogated by RBPJ deficiency. Based on these findings, we administered dichloroacetate (DCA), a pan-PDK inhibitor, in TAD mice, and found that DCA significantly attenuated BAPN-induced TAD in mice. Therefore, our results demonstrate that RBPJ is required for pro-inflammatory moMFs activation, likely by mediating mechanotransduction-induced glycolysis via PDK1 upregulation, and PDK1 inhibitors such as DCA are potential therapeutics for TAD.

Keywords

Dichloroacetate; Glycolysis; Macrophages; RBPJ; Thoracic aortic dissection.

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