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Updated: Mar 20, 2026
Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion
Published on: May 16, 2025
Targeting Endothelial PDK4-EndoMT Feedback Loop Mitigates the Development of Thoracic Aortic Dissection in Mice
Xiangyu Cao1,2, Xingyou Guo1,2,3, Haoyue Huang1,2
1Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Affiliated Hospital (X.C., X.G., H.H., H.S., J.Z., Y.G., T.W., Z.X., C.T., L.Y., L.S., Y.Y., Z.S.), Soochow University, Suzhou, China.
Pyruvate dehydrogenase kinase 4 (PDK4) drives pathological endothelial-to-mesenchymal transition (EndoMT) in thoracic aortic dissection (TAD). Inhibiting PDK4 or its downstream effects can treat TAD by preserving vascular integrity.
Area of Science:
- Cardiovascular Biology
- Vascular Biology
- Cell Fate Determination
Background:
- Thoracic aortic dissection (TAD) is a life-threatening vascular condition with high mortality.
- The role of endothelial-to-mesenchymal transition (EndoMT) in TAD pathogenesis is not well understood.
- The specific function of pyruvate dehydrogenase kinase 4 (PDK4) in driving EndoMT in TAD remains unelucidated.
Purpose of the Study:
- To investigate the mechanistic role of EndoMT in TAD.
- To identify key molecular drivers of EndoMT in TAD.
- To explore PDK4 as a potential therapeutic target for TAD.
Main Methods:
- Integrated transcriptomic profiling and immunofluorescence in human and murine aortic tissues.
- RNA-sequencing and ChIP assays to identify PDK4 as an EndoMT effector.
- Utilized EC-specific knockout mice, AAV-mediated gene modulation, and ELISA for endothelial injury markers.
- Assessed therapeutic potential using the PDK4 inhibitor dichloroacetate.
Main Results:
- Activated EndoMT gene program observed in human and murine TAD specimens.
- PDK4 identified as a critical mediator upregulated during EndoMT, driven by SNAI1.
- PDK4 promotes EndoMT via lactate accumulation, creating a positive feedback loop.
- EC-specific Pdk4 overexpression induced aortic dissection; Pdk4 inhibition attenuated TAD progression and improved survival.
Conclusions:
- Pathological EndoMT in ECs is activated by PDK4, exacerbating TAD.
- PDK4 acts as a key driver of EndoMT in TAD.
- PDK4 represents a promising therapeutic target for thoracic aortic dissection.
